Updated:
22nd May â22 (Berberine)
19th June â22 (Piperine to increase bioavailability of therapeutics; Artemisinin therapeutic efficacy in the experimental model of multiple sclerosis)
23rd June â22 (Various therapeutics, dosing guidance and other relevant studies added, including for treating peripheral neuropathies)
19th July â22 (Citicoline: A Candidate for Adjunct Treatment of Multiple Sclerosis)
17th November â22 (Baicalin)
6th January â23 (Contents page. Browser support varies. Icariin)
25th June '23 (Quick reference: Therapeutics with remyelination properties)
Any extracts used in the following article are for non commercial research and educational purposes only and may be subject to copyright from their respective owners.
Contents:
Quick reference: Therapeutics with remyelination properties
Effect of curcumin on diabetic peripheral neuropathic pain
Sweet Wormwood (Artemisia annua)
Chinese Skullcap (Scutellaria baicalensis) and Baicalin
Introduction
MS differs significantly from PN in the nerve branches affected. Causative factors may well be very different - I 100% agree you must address any underlying causes first, eg diabetes.
That aside, common inflammatory & autoimmune pathways provide an avenue for broad spectrum therapeutics to be of value at often lower cost, over longer periods with potentially greater efficacy and less long term side effects than with some allopathic medicines.
The Link Between Multiple Sclerosis and Peripheral Neuropathy
Peripheral Neuropathy & Multiple Sclerosis Basics
The first thing that must be addressed about peripheral neuropathy and multiple sclerosis is that they are both conditions that deal with the nerves. However, they do not deal with the same set of nerves. Peripheral neuropathy is as its name statesâit affects only the nerves in the periphery of the body. That is, those that are outside the brain and spinal cord. Typically, these would be the ones in the feet, hands, and lower legs.
Meanwhile, MS deals with the nerves of the central nervous system. This means that it affects the nerves in your brain, spinal cord, and optic nerve. Here, the nerves sustain damage over time which causes an interference between the peripheral nervous system and the central nervous system. The damage then causes abnormal sensations, pain, and numbness that can be considered indistinguishable from that caused by peripheral neuropathy.
That is why it is so critical that you have your nerve pain looked at by a doctor. It is not just a matter of a frayed nerve. Rather, it is a complicated diagnosis wherein the doctor must not only determine whether you have MS or peripheral neuropathy but must then determine what of the over one hundred types of peripheral neuropathy or four types of MS you have.
MS & Peripheral Neuropathy Symptoms
MS and peripheral neuropathy have very different underlying causes and as a result, may produce slightly varying symptoms. For instance, diabetes is the most common cause of peripheral neuropathy in America but other culprits are alcohol abuse, HIV infection, and chronic kidney disease. On the other hand, the most common MS is caused by lesions in the brain and spinal cord that result from inflammation from a personâs immune system attacking the myelin sheath of particular nerves.
With different underlying causes, different courses of treatment will be selected. For those who exhibit peripheral neuropathy symptoms, they can end up receiving neuropathy treatment in the way of simply addressing the cause itself. For instance, in the case of diabetes, your doctor would focus on getting your blood sugar under control. In the case of MS, you would receive medications to combat the inflammation which causes the lesions and medications to manage symptoms.
https://www.ncexcellence.com/peripheral-neuropathy-symptoms-and-ms
I could almost copy and paste the âTherapeutics for Long Covid & Transfection Sequalaeâ post:
If I were marketing these in a web store I could probably sell them for cardiovascular disease, cancer therapy or diabetes too and multiply my sales. It's no coincidence I regularly take many of them for cardiovascular health and immune support.
They aren't magic beans that can cure you overnight but there is research behind them and many patients who report them to be beneficial.
They can be prophylactic, complementary, reduce symptoms or slow progression but at low cost and generally benign side effect profiles longer term. So here we are.
See the pattern here: the same antioxidant, antiflammatory, mostly anticancer therapeutics: Glucosamine derivatives, CBD/THC, turmeric, Metformin, Ivermectin, HCQ, Quercetin, Resveratrol, Silymarin, NAC, Q10 & K2. There are others too which help similarly.
Silymarin, piperine and vitamin C all act to increase the bioavailability of many therapeutics from the gut as well as being therapeutic in their own right.
A combination of two or more nootropic substances is called a âstack."
Combining several compounds into a stack can have synergistic effects, such as in the cases of the ingredients in green tea and coffee.
Combine Nootropics Into a "Stack?â, (2020),
For the full list and biochemistry research please read on and follow up the references, but here are a few basic stack components which are commonly taken by sufferers and many should be of therapeutic value.
Although almost all are food or of plant origin originally, with excellent safety profiles, usual cautions apply as with any med.
Start by taking each in isolation at the lowest dose and take for a week, then start combining.
Don't expect instant miracles, these can take time to act systemically as your immune system and cellular health & metabolism recovers & gut biota stabilise.
Check with your doctor first if you are on any other meds for contraindications, have allergies to certain food groups etc and never just stop a med without consultation.
Check on webMD and other sites for cautions etc. These are good places to start:
Let's take turmeric: https://www.webmd.com/vitamins/ai/ingredientmono-662/turmeric
Check the botanical institute site for the same and dosage etc:
https://botanicalinstitute.org/turmeric/#more-2573
Healthline:
https://www.healthline.com/nutrition/turmeric-vs-curcumin#curcumin
Vitamin K2, MK-7, âfermentedâ or extracted from Natto for trans isomer. Even better with 5-10mg piperine. Take 200mg+ per day with meal or fatty food.
Take with D, magnesium, zinc, (ideally zinc with copper) as these are complementary for calcium management: out of your cardiovascular system and back in to teeth & bones eg via a daily multivitamin mineral sup. Zinc is also an essential complement to zinc ionophores like hydroxychloroquine & quercetin (hat-tip to the late Dr. Vladimir Zelenko's protocols).
500mg - 2000mg milk thistle with 80% silymarin. Take at same time with:
Q10 30mg+ for cardiovascular & muscles.
Quercetin 500-1000mg +
- Take quercetin with vitamin C and zinc, as above, for synergistic effects.
Resveratrol 250-500mg +
Hemp or CBD 1 gram = 1 teaspoon dried leaves as a tea or as oil do not exceed 60-70mg in total per day.
https://www.goodhemp.com/hemp-hub/cbd-oil-dosages-explained-how-much-cbd-to-take/
Turmeric as above is also broad spectrum in efficacy. Take with 5-10mg piperine or 375mg black pepper.
Further support:
Artemisia is consumed on a daily basis in many African countries as an effective prophylactic against malaria & HIV.
Add to the above stack berberine or goldenseal 1000mg (750-2000 range). Ivermectin if you can get it but Berberine is just as good by many accounts.
Or/and at another part of the day Sweet Wormwood, Artemisia annua (NOT toxic Common Wormwood, A. absinthium) as 1 teaspoon dried leaves in porridge, as tea, or as infusion. It's bitter so add peppermint or fennel if needed.
Tincture, added to tea:
Take 0.7 - 2.0mL two to four times per day of a 1:4 tincture (in 50% alcohol).
Infusion:
To make an infusion, pour 1 cup boiling water over 1 teaspoon of dried leaf and infuse for 10-15 minutes. For therapeutic use it is recommended to drink 2 to 4 cups a day.
N-Acetyl Cysteine (NAC), 600mg once or twice a day.
Quick reference: Therapeutics with remyelination properties
Querectin (sic) improves myelin repair of optic chiasm in lyolecithin-induced focal demyelination model, (2018)
Abstract
Although the beneficial effects of quercetin on oligodendrocyte precursor cell (OPCs) population has been evaluated in-vitro, there are few studies about the effects of quercetin on myelin repair in the context of demyelination. The aim of this study was to investigate the effects of querectin on functional recovery and myelin repair of optic chiasm in lysolecithin (LPC)-induced demyelination model. Demyelination was induced by local injection of LPC 1% (2 Îźl) into rat optic chiasm. Querectin at doses 25 or 50 mg/kg was administrated daily by oral gavage for 7 or 14 days post LPC. Visual evoked potential (VEPs) recordings were used to assess the functional property of the optic pathway. Immunostaining and myelin staining were performed on brain sections 7 or 14 days post lesion. Electrophysiological data indicated that LPC injection increased the latency of VEPs waves and quercetin effectively reduced the delay of visual signals. The level of glial activation was alleviated in animals under treatment of quercetin compared to vehicle group. Furthermore, quercetin treatment decreased the extent of demyelination areas and increased the remyelination process following LPC injection. Overall, our findings indicate that quercetin could remarkably improve the functional recovery of the optic pathway by its protective effects on myelin sheath and attenuation of glial activation.
Keywords: Demyelination; Glial activation; Optic chiasm; Quercetin; Remyelination; Visual evoked potential.
https://pubmed.ncbi.nlm.nih.gov/29501770/
Baicalin Promotes CNS Remyelination via PPARÎł Signal Pathway, (2022).
Abstract
Background and Objectives
Demyelinating diseases in the CNS are characterized by myelin sheath destruction or formation disorder that leads to severe neurologic dysfunction. Remission of such diseases is largely dependent on the differentiation of oligodendrocytes precursor cells (OPCs) into mature myelin-forming OLGs at the demyelinated lesions, which is defined as remyelination. We discover that baicalin (BA), a natural flavonoid, in addition to its well-known antiinflammatory effects, directly stimulates OLG maturation and CNS myelin repair.
Methods
To investigate the function of BA on CNS remyelination, we develop the complementary in vivo and in vitro models, including physiologic neonatal mouse CNS myelinogenesis model, pathologic cuprizone-induced (CPZ-induced) toxic demyelination model, and postnatal OLG maturation assay. Furthermore, molecular docking, pharmacologic regulation, and transgenic heterozygous mice were used to clarify the target and action of the mechanism of BA on myelin repair promotion.
Results
Administration of BA was not only merely effectively enhanced CNS myelinogenesis during postnatal development but also promoted remyelination and reversed the coordination movement disorder in the CPZ-induced toxic demyelination model. Of note, myelin-promoting effects of BA on myelination or regeneration is peroxisome proliferator-activated receptor Îł (PPARÎł) signaling-dependent.
Discussion
Our work demonstrated that BA promotes myelin production and regeneration by activating the PPARÎł signal pathway and also confirmed that BA is an effective natural product for the treatment of demyelinating diseases.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8808354/
Î9-Tetrahydrocannabinol promotes functional remyelination in the mouse brain, (2021)
Abstract
Background and purpose
Research on demyelinating disorders aims to find novel molecules that are able to induce oligodendrocyte precursor cell differentiation to promote central nervous system remyelination and functional recovery. Î9-Tetrahydrocannabinol (THC), the most prominent active constituent of the hemp plant Cannabis sativa, confers neuroprotection in animal models of demyelination. However, the possible effect of THC on myelin repair has never been studied.
Experimental approach
By using oligodendroglia-specific reporter mouse lines in combination with two models of toxin-induced demyelination, we analysed the effect of THC on the processes of oligodendrocyte regeneration and functional remyelination.
Key results
We show that THC administration enhanced oligodendrocyte regeneration, white matter remyelination and motor function recovery. THC also promoted axonal remyelination in organotypic cerebellar cultures. THC remyelinating action relied on the induction of oligodendrocyte precursor differentiation upon cell cycle exit and via CB1 cannabinoid receptor activation.
Conclusions and implications
Overall, our study identifies THC administration as a promising pharmacological strategy aimed to promote functional CNS remyelination in demyelinating disorders.
https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.15608
Icariin enhances remyelination process after acute demyelination induced by cuprizone exposure, (2017)
Abstract
Pathology are still progressive and cumulative in the remission course of relapsing-remitting MS (RRMS), thus drug treatment during the remission period may play a great role for the regeneration of the myelin sheath. C57BL/6 mice were fed with cuprizone (CPZ, 0.2% w/w) for 5 weeks to induce acute demyelination and oligodendrocytes degeneration, after which CPZ was withdrawn to allow recovery. Icariin (ICA, 6.25, 12.5 and 25mg/kg/day), vehicle (0.5% sodium carboxymethyl cellulose solution) or water was administrated orally to mice for 1 week after CPZ withdrawal. Luxol-fast blue (LFB), immunohistochemical or immunofluorescence staining was used to detect morphological and biological changes in the brains. CPZ administration for 5 weeks resulted in completely demyelination and remyelination occurred when CPZ was withdrawn. ICA treatment during the recovery period for 1 week significantly improved myelin restoration, enhanced NF200-positive axons repair, increased the number of APC+/Olig2+ mature oligodendrocytes and prevented neuron-derived neurotrophic factor such as nerve growth factor (NGF) loss. Our results demonstrated that ICA treatment during the recovery period promotes remyelination and axon rewrapped, at least, in part, by promoting oligodendrogenesis and neurotrophic factor production.
Keywords: Cuprizone; Demyelination; Multiple sclerosis; Myelin; Oligodendrogenesis.
https://pubmed.ncbi.nlm.nih.gov/28161197/
Curcumin promotes oligodendrocyte differentiation and their protection against TNF-Îą through the activation of the nuclear receptor PPAR-Îł, (2021)
Abstract
Curcumin is a compound found in the rhizome of Curcuma longa (turmeric) with a large repertoire of pharmacological properties, including anti-inflammatory and neuroprotective activities. The current study aims to assess the effects of this natural compound on oligodendrocyte progenitor (OP) differentiation, particularly in inflammatory conditions. We found that curcumin can promote the differentiation of OPs and to counteract the maturation arrest of OPs induced by TNF-Îą by a mechanism involving PPAR-Îł (peroxisome proliferator activated receptor), a ligand-activated transcription factor with neuroprotective and anti-inflammatory capabilities. Furthermore, curcumin induces the phosphorylation of the protein kinase ERK1/2 known to regulate the transition from OPs to immature oligodendrocytes (OLs), by a mechanism only partially dependent on PPAR-Îł. Curcumin is also able to raise the levels of the co-factor PGC1-Îą and of the cytochrome c oxidase core protein COX1, even when OPs are exposed to TNF-Îą, through a PPAR-Îł-mediated mechanism, in line with the known ability of PPAR-Îł to promote mitochondrial integrity and functions, which are crucial for OL differentiation to occur. Altogether, this study provides evidence for a further mechanism of action of curcumin besides its well-known anti-inflammatory properties and supports the suggested therapeutic potential of this nutraceutical in demyelinating diseases.
https://www.nature.com/articles/s41598-021-83938-y
N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation, (2020)
Abstract
Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-Îą cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.
Keywords: N-glycan branching, N-acetylglucosamine, oligodendrocytes, myelination, myelin repair, multiple sclerosis, N-linked glycosylation, oligodendrocyte, myelin, metabolism, oligodendrocyte precursor cell
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762951/
Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells, (2019)
Summary
The age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age. Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation. This decline in functional capacity is associated with hallmarks of cellular aging, including decreased metabolic function and increased DNA damage. Fasting or treatment with metformin can reverse these changes and restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination. Aged OPCs treated with metformin regain responsiveness to pro-differentiation signals, suggesting synergistic effects of rejuvenation and pro-differentiation therapies. These findings provide insight into aging-associated remyelination failure and suggest therapeutic interventions for reversing such declines in chronic disease.
Keywords: aging, remyelination, CNS regeneration, adult stem cell, oligodendrocyte progenitor cell, rejuvenation, metformin, dietary restriction
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863391/
Glucosamine
This sort of interaction tends be more effective over longer timescales and works better with other therapeutics, synergy:
Glucosamine-like supplement suppresses multiple sclerosis attacks, study suggests (2011)
UCI's Dr. Michael Demetriou, Ani Grigorian and others found that oral N-acetylglucosamine (GlcNAc), which is similar to but more effective than the widely available glucosamine, inhibited the growth and function of abnormal T-cells that in MS incorrectly direct the immune system to attack and break down central nervous system tissue that insulates nerves.
Study results appear online in the Journal of Biological Chemistry.
More:
A more recent study using the same derivative of glucosamine, showing significant efficacy for remyelination in a mouse study:
N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation (2020)
Abstract
Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-Îą cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS.
Keywords: N-acetylglucosamine; N-glycan branching; N-linked glycosylation; metabolism; multiple sclerosis; myelin; myelin repair; myelination; oligodendrocyte; oligodendrocyte precursor cell; oligodendrocytes.
GlcNAc and N-glycan branching promote primary myelination in mice
Next, we examined whether oral GlcNAc can cross the blood-brain barrier to promote oligodendrocyte differentiation and myelination in vivo. Adult mice (n = 6) and lactating mothers were provided with/without 13C-labeled GlcNAc ([U13C]GlcNAc) (10) in their drinking water, and metabolites derived from perfused brains were analyzed by liquid chromatographyâtandem mass spectrometry (LCâMS/MS). Although this method does not resolve stereoisomers of N-acetylhexosamines (i.e. GlcNAc versus GalNAc), a reversible 4-epimerase equilibrates UDP-GlcNAc and UDP-GalNAc in vivo (19). LCâMS/MS identified UDP-[U13C]-N-acetylhexosamines (UDP-[U13C]-HexNAc) in treated adult female mouse brains and in the brains of their suckling pups (Fig. 2A). This demonstrates that orally delivered GlcNAc is not only able to cross the blood-brain barrier and be metabolized to UDP-GlcNAc by CNS cells but is also secreted at sufficient levels in breast milk to raise UDP-GlcNAc in the brains of suckling pups.
Concentrations of GlcNAc required to raise N-glycan branching in vivo are markedly lower than those required for in vitro activity (37, 38). This is largely driven by GlcNAc entering cells by macropinocytosis, and therefore both time and rate of membrane turnover can influence concentrations of GlcNAc required to raise N-glycan branching (37, 38). Thus, short-term in vitro experiments require high concentrations to raise intracellular GlcNAc levels quickly, whereas primary cells remain viable. In contrast, cells can be exposed to GlcNAc over a longer time period in vivo, allowing lower concentrations to be effective at raising N-glycan branching. The rate of macropinocytosis may also be much higher in vivo compared with in vitro.
GlcNAc is also known to be highly safe in humans. In addition to breastfed infants consuming significant quantities, large intravenous doses of GlcNAc (20 g and 100 g) in humans demonstrated no toxicity issues and no alterations in blood glucose or insulin (63, 64). Moreover, treatment with insulin had no effect on the serum t1/2 of GlcNAc (63). Oral GlcNAc (3â6 g/day) has also been used in 12 children with inflammatory bowel disease for âź2 years without reported toxicities and/or side effects (65). In rats, chronic systematic toxicological studies at doses of 2323â2545 mg/kg/day for up to 114 weeks found no toxicity (66, 67). Coupled with availability as a dietary supplement, oral GlcNAc may provide a potent, inexpensive, and safe therapy for MS. Large double-blind placebo-controlled trials are warranted to investigate this hypothesis.
https://pubmed.ncbi.nlm.nih.gov/33453988/
Related research, relevant to turning down autoimmune histopathology, shows that glucosamine is an alternative to corticosteroids and a safer long term therapeutic for rheumatoid arthritis (RA) and, as above, possibly for MS too. But if you are already immunosuppressed it may be contraindicated:
Immunosuppressive Effects of Glucosamine (2002)
Glucosamine is a naturally occurring derivative of glucose and is an essential component of glycoproteins and proteoglycans, important constituents of many eukaryotic proteins. In cells, glucosamine is produced enzymatically by the amidation of glucose 6-phosphate and can then be further modified by acetylation to result in N-acetylglucosamine. Commercially, glucosamine is sold over-the-counter to relieve arthritis. Although there is evidence in favor of the beneficial effects of glucosamine, the mechanism is unknown. Our data demonstrate that glucosamine suppresses the activation of T-lymphoblasts and dendritic cells in vitroas well as allogeneic mixed leukocyte reactivity in a dose-dependent manner. There was no inherent cellular toxicity involved in the inhibition, and the activity was not reproducible with other amine sugars. More importantly, glucosamine administration prolonged allogeneic cardiac allograft survival in vivo. We conclude that, despite its documented effects on insulin sensitivity, glucosamine possesses immunosuppressive activity and could be beneficial as an immunosuppressive agent.
More:
Mixed results in this study using glucosamine itself, more research advised:
Effects of adjunct glucosamine sulfate on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized, placebo-controlled trial (2010)
Abstract
Objectives: Glucosamine has been safely used to relieve osteoarthritis. The aim of this preliminary study was to evaluate the effect of glucosamine sulfate in combination with current disease modifying therapy on the prevention of progression of relapsing-remitting multiple sclerosis (RRMS).
Methods: A phase II double-blind placebo-controlled randomized clinical trial conducted between February and October 2007 included 97 patients with confirmed RRMS aged 17-55 years. They were randomly allocated to receive 6 months of treatment with either oral glucosamine sulfate (1000 mg/day) or placebo combined with disease-modifying therapy. Response to treatment was assessed at 6 months. Primary and secondary outcome measures were number of relapse and changes in mean Expanded Disability Status Scale (EDSS).
Results: In 46 patients treated with glucosamine sulfate, mean (SD) relapse rate decreased from 1.1 (0.7) at baseline to 0.4 (0.5) at the end of study period (P<0.05). In the 51 patients treated with placebo, the mean (SD) relapse rate did not change. After 6 months, 63.0% of patients receiving glucosamine sulfate remained relapse-free compared to 54.9% of those given placebo (P>0.05). Average EDSS at the end of trial did not differ between groups (mean difference: -0.1; 95% CI: -0.5-0.2).
Discussion: Adding glucosamine sulfate to routine disease modifying-therapy had no significant effect on relapse rate or disease progression during the treatment period. A larger phase-III multicenter study of glucosamine sulfate in RRMS is warranted to more assess the efficacy of this intervention.
https://pubmed.ncbi.nlm.nih.gov/20223094/
Cannabinoids
About cannabis and MS
There are different types of cannabis and cannabis products. One cannabis-based medicine, called Sativex, is licensed in the UK to treat spasticity (muscle spasms and stiffness) in multiple sclerosis (MS).
Cannabis is made up of compounds called cannabinoids. The main ones studied for their therapeutic effect are tetrahydrocannabinol (THC), which gets you âhighâ, and cannabidiol (CBD), which doesnât.
Different types of cannabis
Recreational cannabis
Cannabis thatâs grown and sold illegally comes in these main types:
Marijuana or âweedâ (the plantâs dried leaves and flowers). These days the most common type is skunk, a very strong strain of cannabis with high levels of THC.
Hash (the drug in its smokeable resin form).
Cannabis oils.
Depending on the type, the main ways you take it are by smoking, vapourising (breathing in after heating it) or eating it in things like cakes.
Unlicensed medicinal cannabis products
There are products made using the CBD chemical found in cannabis. These include oils you take by mouth (for example, under your tongue or with a mouth spray) or by vapourising. They wonât get you high as they have little or no THC in them.
The law now says that these oils can be prescribed for medicinal use, but this is on a case-by-case basis and only when there is a special clinical need for individual people. You may see them still being sold as âfood supplementsâ (Reference 1).
Itâs not against the law to have these products if they only have CBD in them (and no THC). (Reference 2)
Licensed medical cannabis products
In the UK there are three licensed cannabis-based medicines:
Epidyolex - licensed for use in two rare kinds of epilepsy.
Nabilone (brand name Cesamet) â a drug cancer patients take to stop them feeling sick during chemotherapy. Nabilone has an artificial version of THC in it. It doesnât have a licence to be used for MS but some doctors prescribe it for MS pain or muscle spasms.
Sativex (brand name for the drug nabiximols) - the only drug made from cannabis thatâs licensed to treat spasticity (muscle spasms and stiffness) in MS. Itâs a mouth spray made from an equal mix of THC and CBD.
As of late 2021 Sativex is approved on the NHS in England for âmoderateâ to âsevereâ spasticity â if other treatments donât work. In Wales it has been approved like this since 2014, and in Northern Ireland since 2021. We hope itâll soon be approved in Scotland, too.
Getting treatments on the NHS doesnât just depend on a recommendation from NICE or from the Scottish Medicines Consortium, which makes these decisions in Scotland. It might still be difficult to get because the NHS in some regions might not agree to pay for it, or local prescribers decide not to give it to people.
Find out about our campaign to improve access to Sativex and read our 2021 Approved but Denied Sativex report
How cannabis can affect you
You canât be sure how strong cannabis is when you buy it illegally or what it might be mixed with. So its effects might not always be the same. As well as the effects you might want, cannabis can cause less welcome changes:
dizziness
sleepiness
feeling drunk
impaired driving
feeling sick
anxiety
increased risk of seizures
harm to unborn babies
High doses may slow down reaction time, change your blood pressure and heart beat and affect your sight and coordination.
Smoking cannabis long term can affect your lungs and raise your heart attack and cancer risk. Itâs possible to become dependent on cannabis, especially if you use it regularly.
If you or your family have a history of mental health problems (such as schizophrenia or bipolar disorder), using cannabis can trigger these or make them worse.
Smoking cannabis mixed with tobacco has the well-known risks of tobacco smoking but has extra risks for people with MS. Smoking tobacco can:
speed up how fast you go from relapsing MS to secondary progressive MS
make some MS drugs (disease modifying therapies) work less well.
Some studies of people with MS who regularly smoke cannabis show they do worse in tests measuring their memory and how fast they process information. MRI scans have also shown abnormal brain activity. None of this is seen in people who use the cannabis-based drug Sativex.
Research into cannabis
When they looked at the research in 2014, the American Academy of Neurology (AAN) didnât find enough evidence that smoking cannabis was safe or effective against MS. They did find that people with MS said cannabis-based drugs (pills or sprays) helped with muscle stiffness (spasticity) and pain.(Reference 3)
A review by Americaâs National Academies of Sciences, Engineering and Medicine (NASEM) in 2017 found that people who took cannabis-based treatment by mouth said it helped with their spasticity. (Reference 4) When their spasticity was tested it was less clear if it had got better.
Our medical advisers believe that about 1 in every 10 people with MS who have pain or muscle spasticity might benefit from cannabis treatment, when other treatments for these symptoms haven't worked. But smoking cannabis, especially if mixed with tobacco, is harmful to the health of people with MS.
More:
https://www.mssociety.org.uk/about-ms/treatments-and-therapies/cannabis/about-cannabis-and-ms
Cannabidiol to Improve Mobility in People with Multiple Sclerosis (2018)
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that affects an estimated 2.3 million people worldwide (1). The symptoms of MS are highly varied but frequently include pain, muscle spasticity, fatigue, inflammation, and depression. These symptoms often lead to reduced physical activity, negatively impact functional mobility, and have a detrimental impact on patientsâ quality of life. Although recent years have seen significant advances in disease modifying therapy, none of the current treatments halts or cures MS related symptoms (2). As a consequence, many people with MS (PwMS) look for alternative and complementary therapies such as cannabis.
The cannabis plant contains many biologically active chemicals, including ~60 cannabinoids (3). Cannabidiol (CBD) and Î9-tetrahydrocannabinol (THC) are typically the most concentrated chemical components of cannabis and believed to primarily drive therapeutic benefit. There is evidence that CBD has a number of beneficial pharmacological effects (4, 5). It is anti-inflammatory, antioxidative, antiemetic, antipsychotic, and neuroprotective. The review of 132 original studies by Bergamaschi et al. (6) describes the safety profile of CBD by highlighting that catalepsy is not induced and physiological parameters (heart rate, blood pressure, and body temperature) are not altered. Moreover, psychomotor and psychological functions are not negatively affected. High doses of up to 1,500âmg per day and chronic use have been repeatedly shown to be well tolerated by humans (6). Additionally, there is also evidence that CBD may reduce the negative psychotropic effects, memory impairment, and appetite stimulation, anxiety and psychotic-like states of THC while enhancing its positive therapeutic actions (7, 8).
Currently, many PwMS utilize cannabis to manage a variety of symptoms. Kindred et al. (9) showed in a web-based survey, which was hosted by the National Multiple Sclerosis Society that 66% of PwMS currently use cannabis for symptom treatment. Furthermore, a study from Canada found that approximately 50% of PwMS would consider the usage of cannabis if the legal status is clear and scientific evidence is available (10). Cannabis is legal in twenty-nine states for the use of specific medical conditionsâincluding MS. Sixteen more states have passed laws that explicitly allow the medical use of CBD. It is suggested that recent increases in the social acceptance of CBD will lead to increases in the number of PwMS using cannabis to treat their symptoms. Anecdotal reports indicate that an increasing number of PwMS use cannabis (medical marijuana) as a supplement to improve their mobility.
Based on the following considerations, it is our opinion that CBD supplementation maybe advisable for PwMS to reduce fatigue, pain, spasticity, and ultimately improve mobility. An overview of the potential impacts of CBD on mobility of PWMS is show in Figure âFigure11.
More:
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5874292/#__ffn_sectitle
Curcumin (turmeric)
Therapeutic potential of curcumin for multiple sclerosis (2018)
Abstract
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS), characterized by demyelination, neuronal injury, and breaching of the blood-brain barrier (BBB). Epidemiological studies have shown that immunological, genetic, and environmental factors contribute to the progression and development of MS. T helper 17 (Th17) cells are crucial immunological participant in the pathophysiology of MS. The aberrant production of IL-17 and IL-22 by Th17 cells crosses BBB promotes its disruption and interferes with transmission of nerve signals through activation of neuroinflammation in the CNS. These inflammatory responses promote demyelination through transcriptional activation of signal transducers and activators of transcription-1 (STAT-1), nuclear factor kappa-B (NF-ÎşB), matrix metalloproteinases (MMPs), interferon Ď (IFNĎ), and Src homology region 2 domain-containing phosphatase-1 (SHP-1). B cells also contribute to disease progression through abnormal regulation of antibodies, cytokines, and antigen presentation. Additionally, oxidative stress has been known as a causative agent for the MS. Curcumin is a hydrophobic yellowish diphenolic component of turmeric, which can interact and modulate multiple cell signaling pathways and prevent the development of various autoimmune neurological diseases including MS. Studies have reported curcumin as a potent anti-inflammatory, antioxidant agent that could modulate cell cycle regulatory proteins, enzymes, cytokines, and transcription factors in CNS-related disorders including MS. The current study summarizes the reported knowledge on therapeutic potential of curcumin against MS, with future indication as neuroprotective and neuropharmacological drug.
Keywords: Autoimmunediseases; B cells; Curcumin; Multiple sclerosis; Oxidative stress; Th-17cells.
https://pubmed.ncbi.nlm.nih.gov/29079885/
Added 19th June â22:
Piperine
Piperine increases the bioavailability of many therapeutics:
In humans, curcumin bioavailability was increased by 2,000% at 45 minutes after co-administering curcumin orally with piperine, whereas in rats, it has been found that concomitant administration of piperine 20 mg/kg with curcumin 2 g/kg increased the serum concentration of curcumin by 154% for a short period of 1-2 hours post drug. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.
Piperine itself is quite expensive, but black pepper, the teaspoon of peppercorns you grind into a curry etc, is within everyone's reach!
Black or white peppers, 0.3-0.5g ground down is all you need per day, taken with curcumin etc.
References:
Recent Developments in Delivery, Bioavailability, Absorption and Metabolism of Curcumin: the Golden Pigment from Golden Spice, (2014),
https://supplements.selfdecode.com/blog/black-pepper-piperine/
https://steenbergs.co.uk/blog/piperine-content-of-different-peppers
Effect of curcumin on diabetic peripheral neuropathic pain
Related to the above:
Effect of curcumin on diabetic peripheral neuropathic pain: Possible involvement of opioid system (2014)
Abstract
Neuropathic pain is one of the most common complications of diabetes mellitus. As efficacy and tolerability of current therapy for neuropathic pain are not ideal, we need to develop the novel drug for better treatment. Curcumin as a natural flavonoid from Curcuma longa has considerable effects on nervous system such as, antidepressant, antinociceptive and neuroprotective effects. The present study was designed to investigate the effect of curcumin on diabetic peripheral neuropathic pain and possible involvement of opioid system. A single dose of 60 mg/kg streptozotocin was injected intraperitoneally to induce diabetes in rats. STZ-induced diabetic rats were treated with curcumin (50 mg/kg/day) acute and chronically. Thermal hyperalgesia and mechanical allodynia were measured on the days 0, 7, 14 and 21 after diabetes induction as behavioral scores of neuropathic pain. Chronic, but not acute, treatment with curcumin prevents the weight loss and attenuates mechanical allodynia in STZ-induced diabetic rats. Pretreatment with naloxone (1 mg/kg) significantly reduced anti-allodynic effect of chronic curcumin in von Frey filament test. Our results suggest that curcumin can be considered as a new therapeutic potential for the treatment of diabetic neuropathic pain and the activation of opioid system may be involved in the antinociceptive effect of curcumin.
Effects of Curcumin and Its Different Formulations in Preclinical and Clinical Studies of Peripheral Neuropathic and Postoperative Pain: A Comprehensive Review (2021)
Abstract
Lesion or disease of the somatosensory system leads to the development of neuropathic pain. Peripheral neuropathic pain encompasses damage or injury of the peripheral nervous system. On the other hand, 10â15% of individuals suffer from acute postoperative pain followed by persistent pain after undergoing surgeries. Antidepressants, anticonvulsants, baclofen, and clonidine are used to treat peripheral neuropathy, whereas opioids are used to treat postoperative pain. The negative effects associated with these drugs emphasize the search for alternative therapeutics with better efficacy and fewer side effects. Curcumin, a polyphenol isolated from the roots of Curcuma longa, possesses antibacterial, antioxidant, and anti-inflammatory properties. Furthermore, the low bioavailability and fast metabolism of curcumin have led to the advent of various curcumin formulations. The present review provides a comprehensive analysis on the effects of curcumin and its formulations in preclinical and clinical studies of neuropathic and postoperative pain. Based on the positive outcomes from both preclinical and clinical studies, curcumin holds the promise of mitigating or preventing neuropathic and postoperative pain conditions. However, more clinical studies with improved curcumin formulations are required to involve its use as adjuvant to neuropathic and postoperative drugs.
Keywords: curcumin, curcumin formulations, diabetes, peripheral neuropathy, postoperative pain, preemptive analgesia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125634/
Key Developments in the Potential of Curcumin for the Treatment of Peripheral Neuropathies (2022)
Abstract
Peripheral neuropathies (PN) can be triggered after metabolic diseases, traumatic peripheral nerve injury, genetic mutations, toxic substances, and/or inflammation. PN is a major clinical problem, affecting many patients and with few effective therapeutics. Recently, interest in natural dietary compounds, such as polyphenols, in human health has led to a great deal of research, especially in PN. Curcumin is a polyphenol extracted from the root of Curcuma longa. This molecule has long been used in Asian medicine for its anti-inflammatory, antibacterial, and antioxidant properties. However, like numerous polyphenols, curcumin has a very low bioavailability and a very fast metabolism. This review addresses multiple aspects of curcumin in PN, including bioavailability issues, new formulations, observations in animal behavioral tests, electrophysiological, histological, and molecular aspects, and clinical trials published to date. The, review covers in vitro and in vivo studies, with a special focus on the molecular mechanisms of curcumin (anti-inflammatory, antioxidant, anti-endoplasmic reticulum stress (anti-ER-stress), neuroprotection, and glial protection). This review provides for the first time an overview of curcumin in the treatment of PN. Finally, because PN are associated with numerous pathologies (e.g., cancers, diabetes, addiction, inflammatory disease...), this review is likely to interest a large audience.
Keywords: curcumin, peripheral neuropathy, antioxidant, anti-inflammatory, anti-ER-stress, clinical trial
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600446/
Sweet Wormwood (Artemisia annua)
Artemisinin therapeutic efficacy in the experimental model of multiple sclerosis
The results of a murine (mouse) model were encouraging. They found that artemisinin elevated Th2 cell counts antagonised autoimmune Th1 macrophages.
Why this is important. In short it helps stop the body attacking itself:
Type 1 T helper (Th1) cells produce interferon-gamma, interleukin (IL)-2, and tumour necrosis factor (TNF)-beta, which activate macrophages and are responsible for cell-mediated immunity and phagocyte-dependent protective responses. By contrast, type 2 Th (Th2) cells produce IL-4, IL-5, IL-10, and IL-13, which are responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions, thus providing phagocyte-independent protective responses.
Romagnani S. Th1/Th2 cells. Inflamm Bowel Dis. 1999 Nov;5(4):285-94. doi: 10.1097/00054725-199911000-00009. PMID: 10579123.
Abstract
Context: The immune system through T-helper 1 (Th1) and Th17 cells play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), whereas the Th2 responses inhibit myelin degeneration. Artemisinin, as an anti-malaria as its agent, has been used widely in the treatment of malaria, shifts the lymphocyte responses from Th1 to Th2.
Objective: In this study, we have investigated the therapeutic effects of artemisinin on the EAE treatment.
Materials and methods: EAE was induced in the inbred C57BL6 mice. High and low doses of prednisolone and artemisinin were injected daily with the control and test groups, respectively. The spleen and the brain of the mice were removed and used for ELISA and histological studies.
Results: The mean weight of mice was significantly (p value < .05) higher in artemisinin-treated group compared with the untreated group, whereas, the mean EAE score of mice was significantly (p value < .05) lower in the artemisinin-treated group compared with the untreated group. The brain histology shows the absence of plaque formation in the artemisinin treated group. The concentration of IFN-Îł in the low dose of artemisinin treated group showed significantly (p value < .05) lower in comparison to the untreated group. IL-4 concentration was significantly (p value < .05) higher in the treated groups than the control group.
Conclusions: Since, artemisinin can shift the immune responses from Th1 to Th2, therefore, it can be helpful in the treatment of MS after more investigation.
Keywords: Artemisinin; autoimmune diseases; cytokines; experimental autoimmune encephalomyelitis; multiple sclerosis
Khakzad MR, Ganji A, Ariabod V, Farahani I. Artemisinin therapeutic efficacy in the experimental model of multiple sclerosis. Immunopharmacol Immunotoxicol. 2017 Dec;39(6):348-353. doi: 10.1080/08923973.2017.1379087. Epub 2017 Sep 27. PMID: 28952817.
https://pubmed.ncbi.nlm.nih.gov/28952817/
Full literature review:
Metformin
Galega officinalis, commonly known as galega or goat's-rue is a source of the toxin galegine, with similar properties to metformin and indeed this was used as its parent. It gives the herb similar properties but I cannot recommend it yet pending a literature review and toxicity assessments but by all means consult other sources. I will update this page accordingly.
Metformin as a Potential Agent in the Treatment of Multiple Sclerosis
Angela Dziedzic et al. Int J Mol Sci. 2020.
Abstract
Metformin, a synthetic derivative of guanidine, is commonly used as an oral antidiabetic agent and is considered a multi-vector application agent in the treatment of other inflammatory diseases. Recent studies have confirmed the beneficial effect of metformin on immune cells, with special emphasis on immunological mechanisms. Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by various clinical courses. Although the pathophysiology of MS remains unknown, it is most likely a combination of disturbances of the immune system and biochemical pathways with a disruption of blood-brain barrier (BBB), and it is strictly related to injury of intracerebral blood vessels. Metformin has properties which are greatly desirable for MS therapy, including antioxidant, anti-inflammatory or antiplatelet functions. The latest reports relating to the cardiovascular disease confirm an increased risk of ischemic events in MS patients, which are directly associated with a coagulation cascade and an elevated pro-thrombotic platelet function. Hence, this review examines the potential favourable effects of metformin in the course of MS, its role in preventing inflammation and endothelial dysfunction, as well as its potential antiplatelet role.
Keywords: metformin; multiple sclerosis; neurodegeneration.
https://pubmed.ncbi.nlm.nih.gov/32825027/
Metformin and Autoimmunity: A âNew Dealâ of an Old Drug (2018)
Abstract
Metformin (dimethyl biguanide) is a synthetic derivative of guanidine, isolated from the extracts of Galega officinalis, a plant with a prominent antidiabetic effect. Since its discovery more than 50âyears ago, metformin represents a worldwide milestone in treatment of patients with type 2 diabetes (T2D). Recent evidence in humans indicates novel pleiotropic actions of metformin which span from its consolidated role in T2D management up to various regulatory properties, including cardio- and nephro-protection, as well as antiproliferative, antifibrotic, and antioxidant effects. These findings, together with ground-breaking studies demonstrating its ability to prolong healthspan and lifespan in mice, provided the basis for defining metformin as a potential antiaging molecule. Moreover, emerging in vivo and in vitro evidence support the novel hypothesis that metformin can exhibit immune-modulatory features. Studies suggest that metformin interferes with key immunopathological mechanisms involved in systemic autoimmune diseases, such as the T helper 17/regulatory T cell balance, germinal centers formation, autoantibodies production, macrophage polarization, cytokine synthesis, neutrophil extracellular traps release, and bone or extracellular matrix remodeling. These effects may represent a powerful contributor to antiaging and anticancer properties exerted by metformin and, from another standpoint, may open the way to assess whether metformin can be a candidate molecule for clinical trials involving patients with immune-mediated diseases. In this article, we will review the available preclinical and clinical evidence regarding the effect of metformin on individual cells of the immune system, with emphasis on immunological mechanisms related to the development and maintenance of autoimmunity and its potential relevance in treatment of autoimmune diseases.
Keywords: metformin, autoimmunity, autoimmune diseases, T cell, B cell, macrophage, neutrophil, fibroblast
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994909/
Ivermectin
Common Anti-Parasitic Agent Eases Motor Symptoms, Aids Remyelination in MS Mouse (2018)
A common anti-parasitic agent showed a potential to prevent inflammation and to promote nerve cell recovery â remyelination â in a mouse model of multiple sclerosis (MS).
By promoting the activity of a receptor called P2X4R that is present in microglial cells â immune cells that reside in the brain â ivermectin (marketed as Stromectol, or Soolantra) eased the clinical manifestations of experimental autoimmune encephalomyelitis (EAE; an induced autoimmune disease similar to MS in humans).
Specifically, researchers saw evidence suggesting that ivermectin was âa potential candidate among currently used drugs to promote the repair of myelin damage,â they wrote.
Their discovery was reported in the study âP2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis,â published in the journal EMBO Molecular Medicine.
âWe are witnessing a discovery that is opening up a new channel of pharmacological development for the treatment of the progressive phase of multiple sclerosis, and with it we want to open a new door on improving the life quality of people who suffer multiple sclerosis,â MarĂa Domercq, PhD, member of the Achucarro Basque Center for Neuroscience in Spain and senior author of the study, said in a news release.
More:
Hydroxychloroquine
Hydroxychloroquine* for Primary Progressive Multiple Sclerosis
Marcus W Koch et al. Ann Neurol. 2021 Dec.
*Warning of toxicity at higher doses, self medication not advised.
Abstract
Objective: Primary progressive multiple sclerosis (PPMS) does not respond well to immunomodulatory or immunosuppressive treatment. Chronic activation of microglia has been implicated in the pathophysiology of PPMS. The antimalarial drug hydroxychloroquine (HCQ) reduces the activity of human microglia and has neuroprotective effects in vitro.
Methods: We conducted a single-arm, phase II futility trial of 200 mg oral HCQ twice daily for 18 months. In an effort to investigate disability worsening in the absence of overt focal inflammation, we excluded participants with contrast enhancing lesions on a screening magnetic resonance imaging (MRI). The primary end point was âĽ20% worsening on the timed 25-foot walk measured between 6 and 18 months of follow-up.
Results: Based on original trial data, 40% of the cohort were expected to worsen. We used a Simon 2-stage design to compare a null hypothesis of 40% of the cohort worsening against the one-sided alternative of 20%. Using a 5% type 1 error rate and 80% power, HCQ treatment would be deemed successful if fewer than 10 of 35 participants experienced clinically significant worsening. The study met its primary end point, as only 8 of 35 participants worsened between 6 and 18 months. HCQ was overall well-tolerated, with adverse events in 82% and serious adverse events in 12% of participants. All serious adverse events were unlikely related to HCQ use.
Interpretation: HCQ treatment was associated with reduced disability worsening in people with PPMS. HCQ is a promising treatment candidate in PPMS and should be investigated further in randomized controlled clinical trials. ANN NEUROL 2021;90:940-948.
https://pubmed.ncbi.nlm.nih.gov/34590328/
Resveratrol
Resveratrol Promotes Remyelination in Cuprizone Model of Multiple Sclerosis: Biochemical and Histological Study
Heba R Ghaiad et al. Mol Neurobiol. 2017 Jul.
Abstract
Multiple sclerosis (MS) is a demyelinating neurodegenerative disease, representing a major cause of neurological disability in young adults. Resveratrol is a stilbenoid polyphenol, known to pass blood brain barrier and exhibit antioxidant, anti-inflammatory, and neuroprotective effects in several brain injuries. Cuprizone model of MS is particularly beneficial in studying demyelination/remyelination. Our study examined the potential neuroprotective and pro-remyelination effects of resveratrol in cuprizone-intoxicated C57Bl/6 mice. Mice were fed with chow containing 0.7 % cuprizone for 7 days, followed by 3 weeks on 0.2 % cuprizone diet. Resveratrol (250 mg/kg/day, p.o.) was given for 3 weeks starting from the second week. At the end of the experiment, animals were tested on rotarod to evaluate changes in balance and motor coordination. Mice were then sacrificed to measure the brain content of glutathione, lipid peroxidation products, adenosine triphosphate, and phospho-inhibitory subunit of nuclear factor ÎşB-Îą. The activities of cytochrome oxidase and superoxide dismutase were also assessed. The gene expression of myelin basic protein, 2',3'-cyclic nucleotide 3' phosphodiesterase, oligodendrocyte transcription factor-1 (Olig1), NF-ÎşB p65 subunit, and tumor necrosis factor-Îą was also estimated. Luxol fast blue/periodic acid-Schiff stained brain sections were blindly scored to assess the myelin status. Resveratrol effectively enhanced motor coordination and balance, reversed cuprizone-induced demyelination, improved mitochondrial function, alleviated oxidative stress, and inhibited NF-ÎşB signaling. Interestingly, resveratrol increased Olig1 expression that is positively correlated to active remyelination. The present study may be the first to indicate a pro-remyelinative effect for resveratrol which might represent a potential additive benefit in treating MS.
Keywords: Cuprizone; Demyelination; Multiple sclerosis; Olig1; Remyelination; Resveratrol.
https://pubmed.ncbi.nlm.nih.gov/27067589/
Anti-inflammatory effect of resveratrol attenuates the severity of diabetic neuropathy by activating the Nrf2 pathway (2021)
Abstract
The mechanisms underlying the development of neuropathy associated with diabetes mellitus are not fully understood. Resveratrol, as a nonflavonoid polyphenol, plays a variety of beneficial roles in the treatment of chronic diseases such as Alzheimer's disease, coronary heart disease and obesity. In our study, the role of nuclear erythroid 2-related factor 2 (Nrf2) in resveratrol-mediated protection against streptozotocin-induced diabetic peripheral neuropathy (DPN) was investigated, and the antioxidant effect of resveratrol in diabetic peripheral nerves was studied. The STZ-treated model mice were divided into two groups. The resveratrol group was intragastrically administered 10 ml/kg 10% resveratrol once a day until the 12th week after STZ injection. The vehicle-treated mice were injected with the same volume of DMSO. Analysis of the effects of resveratrol in DPN revealed the following novel findings: (i) the pain and temperature sensitivities of diabetic mice were improved after treatment with resveratrol; (ii) Nrf2 expression was increased in the diabetic peripheral nerves of resveratrol-treated mice, and NF-KB pathway inhibition protected nerves upon resveratrol treatment in peripheral neuropathy; and (iii) resveratrol modulated the anti-inflammatory microenvironment of peripheral nerves by increasing Nrf2 activation and the expression of p-p65, and these changes may have been responsible for the neuroprotective effect of resveratrol in DPN, which was confirmed by Nrf2 knockout in diabetic mice. Overall, this study demonstrates that resveratrol may attenuate the severity of DPN by protecting peripheral nerves from apoptosis by inhibiting the NF-KB pathway and increasing Nrf2 expression.
Keywords: Nrf2 pathway; anti-inflammatory; diabetic neuropathy; resveratrol.
https://pubmed.ncbi.nlm.nih.gov/33770763/
N-Acetylglucosamine (NAC)
N-Acetylglucosamine Inhibits T-helper 1 (Th1)/T-helper 17 (Th17) Cell Responses and Treats Experimental Autoimmune Encephalomyelitis (2011)
Current treatments and emerging oral therapies for multiple sclerosis (MS) are limited by effectiveness, cost, and/or toxicity. Genetic and environmental factors that alter the branching of Asn (N)-linked glycans result in T cell hyperactivity, promote spontaneous inflammatory demyelination and neurodegeneration in mice, and converge to regulate the risk of MS. The sugar N-acetylglucosamine (GlcNAc) enhances N-glycan branching and inhibits T cell activity and adoptive transfer experimental autoimmune encephalomyelitis (EAE). Here, we report that oral GlcNAc inhibits T-helper 1 (Th1) and T-helper 17 (Th17) responses and attenuates the clinical severity of myelin oligodendrocyte glycoprotein (MOG)-induced EAE when administered after disease onset. Oral GlcNAc increased expression of branched N-glycans in T cells in vivo as shown by high pH anion exchange chromatography, MALDI-TOF mass spectroscopy and FACS analysis with the plant lectin l-phytohemagglutinin. Initiating oral GlcNAc treatment on the second day of clinical disease inhibited MOG-induced EAE as well as secretion of interferon-Îł, tumor necrosis factor-Îą, interleukin-17, and interleukin-22. In the more severe 2D2 T cell receptor transgenic EAE model, oral GlcNAc initiated after disease onset also inhibits clinical disease, except for those with rapid lethal progression. These data suggest that oral GlcNAc may provide an inexpensive and nontoxic oral therapeutic agent for MS that directly targets an underlying molecular mechanism causal of disease.
https://www.jbc.org/article/S0021-9258(20)50511-5/fulltext
N-acetyl Cysteine Administration Is Associated With Increased Cerebral Glucose Metabolism in Patients With Multiple Sclerosis: An Exploratory Study (2020)
Abstract
Background: Multiple Sclerosis (MS) is an autoimmune disease marked by progressive neurocognitive injury. Treatment options affording neuroprotective effects remain largely experimental. The purpose of this proof of concept study was to explore the effects of N-acetyl-cysteine (NAC) on cerebral glucose metabolism (CMRGlu) and symptoms in patients with multiple sclerosis (MS).
Methods: Twenty-four patients with MS were randomized to either NAC plus standard of care, or standard of care only (waitlist control). The experimental group received NAC intravenously once per week and orally the other 6 days. Patients in both groups were evaluated at baseline and after 2 months (of receiving the NAC or waitlist control period) with an integrated Position Emission Tomography (PET)/ Magnetic Resonance Imaging (MRI) scanner, using 18F Fluorodeoxyglucose (FDG) to measure cerebral glucose metabolism. Following imaging evaluation at 2 months, subjects initially attributed to the standard of care arm were eligible for treatment with NAC. Clinical and symptom questionnaires were also completed initially and after 2 months.
Results: The FDG PET data showed significantly increased cerebral glucose metabolism in several brain regions including the caudate, inferior frontal gyrus, lateral temporal gyrus, and middle temporal gyrus (p < 0.05) in the MS group treated with NAC, as compared to the control group. Self-reported scores related to cognition and attention were also significantly improved in the NAC group as compared to the control group.
Conclusions: The results of this study suggest that NAC positively affects cerebral glucose metabolism in MS patients, which is associated with qualitative, patient reported improvements in cognition and attention. Larger scale studies may help to determine the clinical impact of NAC on measures of functioning over the course of illness, as well as the most effective dosage and dosage regimen.
Keywords: N-acetyl cysteine, antioxidant, multiple sclerosis, cerebral glucose metabolism, positron emission tomography, cognition
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC7033492/#__ffn_sectitle
Physiological Effects of N-Acetyl Cysteine in Patients With Multiple Sclerosis (MSNAC) (2021)
Detailed Description:
The original protocol consisted of two arms. The first arm of this study will receive intravenous and oral NAC, a strong antioxidant that increases brain glutathione. NAC, is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine. It is a common over-the-counter supplement that is also available as an injectable pharmaceutical that protects the liver in cases of acetaminophen overdose. Laboratory studies have displayed some benefits to use of NAC. It has the potential to reduce markers of oxidative damage, protect against cell death, and to increase glutathione in blood, which might be useful in preventing oxidative damage in MS patients.
Full study details, concludes 2023:
https://clinicaltrials.gov/ct2/show/NCT03032601
N-Acetylcysteine: A Review of Clinical Usefulness (an Old Drug with New Tricks) (2021)
Abstract
Objective
To review the clinical usefulness of N-acetylcysteine (NAC) as treatment or adjunctive therapy in a number of medical conditions. Use in Tylenol overdose, cystic fibrosis, and chronic obstructive lung disease has been well documented, but there is emerging evidence many other conditions would benefit from this safe, simple, and inexpensive intervention.
Quality of Evidence. PubMed, several books, and conference proceedings were searched for articles on NAC and health conditions listed above reviewing supportive evidence. This study uses a traditional integrated review format, and clinically relevant information is assessed using the American Family Physician Evidence-Based Medicine Toolkit. A table summarizing the potential mechanisms of action for N-acetylcysteine in these conditions is presented.
Main Message. N-acetylcysteine may be useful as an adjuvant in treating various medical conditions, especially chronic diseases. These conditions include polycystic ovary disease, male infertility, sleep apnea, acquired immune deficiency syndrome, influenza, parkinsonism, multiple sclerosis, peripheral neuropathy, stroke outcomes, diabetic neuropathy, Crohn's disease, ulcerative colitis, schizophrenia, bipolar illness, and obsessive compulsive disorder; it can also be useful as a chelator for heavy metals and nanoparticles. There are also a number of other conditions that may show benefit; however, the evidence is not as robust.
Conclusion
The use of N-acetylcysteine should be considered in a number of conditions as our population ages and levels of glutathione drop. Supplementation may contribute to reducing morbidity and mortality in some chronic conditions as outlined in the article.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211525/
N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases (2016)
Abstract
The treatment of neuropathic pain remains a clinical challenge because of its unclear mechanisms and broad clinical morbidity. Matrix metalloproteinase (MMP)-9 and MMP-2 have previously been described as key components in neuropathic pain because of their facilitation of inflammatory cytokine maturation and induction of neural inflammation. Therefore, the inhibition of MMPs may represent a novel therapeutic approach to the treatment of neuropathic pain. In this study, we report that N-acetyl-cysteine (NAC), which is a broadly used respiratory drug, significantly attenuates neuropathic pain through a unique mechanism of MMP inhibition. Both the in vitro (0.1 mM) and in vivo application of NAC significantly suppressed the activity of MMP-9/2. Orally administered NAC (50, 100, and 200 mg/kg) not only postponed the occurrence but also inhibited the maintenance of chronic constrictive injury (CCI)-induced neuropathic pain in rats. The administration of NAC blocked the maturation of interleukin-1β, which is a critical substrate of MMPs, and markedly suppressed the neuronal activation induced by CCI, including inhibiting the phosphorylation of protein kinase Cγ, NMDAR1, and mitogen-activated protein kinases. Finally, NAC significantly inhibited CCI-induced microglia activation but elicited no notable effects on astrocytes. These results demonstrate an effective and safe approach that has been used clinically to alleviate neuropathic pain through the powerful inhibition of the activation of MMPs.
https://pubmed.ncbi.nlm.nih.gov/27075430/
And for sciatica in a rat study:
N-acetylcysteine (NAC) alleviates the peripheral neuropathy associated with liver cirrhosis via modulation of neural MEG3/PAR2/ NF-ŇĄB axis (2020)
Abstract
Background and aim: Oxidative stress (OS) is accused in pathogenesis of many diseases, including liver cirrhosis by many mechanisms. One of them is the disturbance of long non coding maternally expressed 3 (MEG3)/protease activated receptor 2 (PAR2) downstream pathway. We aimed to investigate the role of this axis in cirrhotic neuropathy and whether an antioxidant compound such as N-acetylcysteine (NAC) could improve the peripheral nerve function through repression of MEG3/PAR2.
Methods: Thirty Wistar rats were used and divided into 5 groups; naive, thiacetamide (TAA) (200 mg/kg 3 times/week. i.p. for 8 weeks) and TAA+NAC (50 or 100 or 200 mg/kg/day) groups. Von Frey (VF) test for mechanical nociceptive responses, hepatic& neural MEG3, NF-ŇĄB and neural PAR2 expression by PCR, histological studies for liver and sciatic nerve together with the dorsopedal skin thickness were done.
Results: TAA induced significant decrease in liver function, negative VF test, an increase in the expression of hepatic& neural MEG3, NF-ŇĄB and neural PAR2. The histological studies showed cirrhotic changes with atrophy of the sciatic nerve and the dorsal skin. NAC improved the liver function together with reversal of the neural: functional, biochemical and histological changes in a dose dependent manner.
Conclusions: NAC could improve the peripheral neuropathy in cirrhotic rat through suppression of MEG3/PAR2 expression.
Keywords: Cirrhosis; MEG3; N-acetylcysteine; Neuropathy; PAR2.
https://pubmed.ncbi.nlm.nih.gov/31751619/
Taking NAC long term is contraindicated against some drugs, particularly chemotherapeutics, due to multidrug resistance:
N-acetylcysteine enhances multidrug resistance-associated protein 1 mediated doxorubicin resistance (2004)
Multidrug resistance (MDR) severely limits the effectiveness of chemotherapy in a variety of common malignancies. Resistance of cancer cells to a single drug is usually accompanied by resistance to other drugs with different structures and cellular targets [1,2]. Identifying the mechanisms leading to intrinsic or acquired drug resistance is important in developing more effective therapies. Many human tumours express MRP1 [3,4]. Multidrug resistance-associated protein 1 extrudes cysteinyl leukotriene and several glutathione S-conjugates, sulphate, and glucuronide-conjugated organic anions from cells [2]. The exact mechanism of MRP1-involved multidrug resistance remains unknown, although GSH is likely to have a role in the resistance reoccurring. Thus, clarifying the mechanism of action of MRP1 in cell lines or tumours overexpressing MRP1 can give new insights to future experiments and therapies.
Doxorubicin is an anthracycline-type antitumour agent and produces free radicals. Multidrug resistance-associated protein 1-mediated drug resistance occurs against doxorubicin, although the mechanisms are not fully understood. Glutathione is the most abundant nonprotein intracellular thiol-containing compound that is a key molecule in MRP1-mediated MDR [1,5]. It is suggested that increased MRP1 expression without an increase in GSH biosynthesis would not cause any drug resistance in tumour cells, but would result in cell death [6]. Glutathione conjugates with drugs catalyzed by the enzyme GST and causes their subsequent removal from the cells [6]. DL-buthionine (S,R)-sulfoximine inhibits GSH synthesis by irreversible inhibition of Îł-glutamyl cysteine synthase and has no other known effect on cells [1,7,8]. N-acetylcysteine is a thiol antioxidant and cysteine source for GSH synthesis [9].
Our results demonstrate that NAC enhances MRP1-mediated doxorubicin resistance and this effect depends on GSH synthesis. DL-buthionine (S,R)-sulfoximine seems a promising chemotherapy improving agent in MRP1 overexpressing tumour cells. Further studies are needed to clarify drug resistance phenomenon and the effectiveness of future chemotherapy regimens in MRP1 overexpressing tumours.
https://pubmed.ncbi.nlm.nih.gov/15473893/
Coenzyme Q10, Co-Q10
Ubiquinol is the reduced form with much greater bioavailability, but cost can be prohibitive. Silymarin increases uptake of the conventional form.
Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: A double blind randomized clinical trial
Meisam Sanoobar et al. Nutr Neurosci. 2016
Abstract
Objectives: Multiple sclerosis (MS) is the chronic inflammatory and demyelinating disorder of central nervous system which is accompanied with disability and negative life style changes such as fatigue and depression. The aim of this study is to investigate the effect of coenzyme Q10 (CoQ10) supplementation on fatigue and depression in patients with MS.
Methods: We performed a randomized, double-blinded, placebo-controlled trial to determine the effect of CoQ10 supplement (500 mg/day) vs. placebo for 12 weeks. Fatigue symptoms were quantified by means of fatigue severity scale (FSS) and the Beck depression inventory (BDI) was used to assess depressive symptoms.
Results: A significant decrease of FSS was observed in CoQ10 group during the intervention (P = 0.001) and significant increase of FSS change was observed within placebo group (P = 0.001). Repeated measure analysis of variance showed a significant time-by-treatment interaction for FSS (baseline 41.5 ¹ 15.6 vs. endpoint 45 ¹ 13.6; F1,45 = 55.23, P < 0.001, Ρ(2) = 0.56) and BDI (baseline 17.8 ¹ 12.2 vs. endpoint 20.4 ¹ 11.4; F1,45 = 40.3, P < 0.001, Ρ(2) = 0.48), indicating significant decrease of FSS and BDI in CoQ10 group compared to placebo group.
Conclusion: Our study suggests that CoQ10 supplementation (500 mg/day) can improve fatigue and depression in patients with multiple sclerosis.
Keywords: Coenzyme Q10; Depression; Fatigue; Multiple sclerosis; Treatment.
https://pubmed.ncbi.nlm.nih.gov/25603363/
Coenzyme Q10 enhances remyelination and regulate inflammation effects of cuprizone in corpus callosum of chronic model of multiple sclerosis (2021)
Abstract
Multiple Sclerosis (MS) is a chronic, progressive demyelinating disease of the central nervous system that causes the most disability in young people, besides trauma. Coenzyme Q10 (CoQ10)-also known as ubiquinone-is an endogenous lipid-soluble antioxidant in the mitochondrial oxidative respiratory chain which can reduce oxidative stress and inflammation, the processes associated with demyelination in MS. Cuprizone (CPZ) intoxication is a well-established model of inducing MS, best for studying demyelination-remyelination. In this study, we examined for the first time the role of CoQ10 in preventing demyelination and induction of remyelination in the chronic CPZ model of MS. 40 male mice were divided into four groups. 3 group chewed CPZ-containing food for 12 weeks to induce MS. After 4 weeks, one group were treated with CoQ10 (150 mg/kg/day) by daily gavage until the end of the experiment, while CPZ poisoning continued. At the end of 12 weeks, tail suspension test (TST) and open field test (OFT) was taken and animals were sacrificed to assess myelin basic protein (MBP), oligodendrocyte transcription factor-1 (Olig1), tumor necrosis factor-Îą (TNF-Îą) and interleukin 6 (IL-6) by real-time polymerase chain reaction (real-time PCR) and total antioxidant capacity (TAC) and superoxide dismutase (SOD) by Elisa test. Luxol fast blue (LFB) staining was used to evaluate histological changes. CoQ10 administration promoted remyelination in histological findings. MBP and Olig-1 expression were increased significantly in CoQ10 treated group compare to the CPZ-intoxicated group. CoQ10 treatment alleviated stress oxidative status induced by CPZ and dramatically suppress inflammatory biomarkers. CPZ ingestion made no significant difference between normal control group and the CPZ-intoxicated group in TST and OFT. CoQ10 can enhance remyelination in the CPZ model and potentially might have same effects in MS patients.
Keywords: Coenzyme Q10; Cuprizone; Multiple sclerosis; Oxidative stress; Remyelination.
https://pubmed.ncbi.nlm.nih.gov/33245472/
Vitamin K2
Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease (2019)
Abstract
Vitamin K is an essential bioactive compound required for optimal body function. Vitamin K can be present in various isoforms, distinguishable by two main structures, namely, phylloquinone (K1) and menaquinones (K2). The difference in structure between K1 and K2 is seen in different absorption rates, tissue distribution, and bioavailability. Although differing in structure, both act as cofactor for the enzyme gamma-glutamylcarboxylase, encompassing both hepatic and extrahepatic activity. Only carboxylated proteins are active and promote a health profile like hemostasis. Furthermore, vitamin K2 in the form of MK-7 has been shown to be a bioactive compound in regulating osteoporosis, atherosclerosis, cancer and inflammatory diseases without risk of negative side effects or overdosing. This review is the first to highlight differences between isoforms vitamin K1 and K2 by means of source, function, and extrahepatic activity.
Keywords: vitamin K1, vitamin K2, vitamin K dependent proteins, vascular calcification
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413124/
Vitamin K2 in multiple sclerosis patients (2018)
Summary
Background
Vitamin K2 (VK2) belongs to the vitamin K family and comprises a number of subtypes differing in length of side chains consisting of isoprenoid groups (menaquinone-n, MK-n). It is essential for a number of physiological functions although the full spectrum of activity has not yet been elucidated. Due to its role in protection of mitochondrial damage, VK2 could be relevant in preventing disease progress in multiple sclerosis (MS).
Methods
We measured VK2 serum levels by the double antibody sandwich Enzyme-linked Immunosorbent Assay (ELISA) technique in MS patients and age and sex matched controls, both under vitamin D supplementation, and related it to disease characteristics and treatment.
Results
Overall, 45 MS patients (31 females and 39 of the relapsing-remitting type) and 29 healthy controls (19 females) were included in the analysis. The MS patients had vastly lower VK2 blood levels than controls (235âŻÂąâ100âŻng/ml vs. 812âŻÂąâ154âŻng/ml, respectively). Female patients had significantly lower VK2 levels than males and a decrease with age by approximately 10% per decade was found. The VK2 levels were lower with increasing numbers of attacks per year and were higher in patients with optic nerve lesions. No consistent relationship with medications was detected.
Conclusion
The substantially lower levels of VK2 in MS patients could be due to depletion, lower production in the gut, diminished absorption or, less likely, reduced intake of precursor vitamin K1. The role of VK2 in MS development and progress deserves further study.
Full paper:
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5966473/
Preliminary Study Shows Positive Effect of Vitamin K2 as MK-7 on Peripheral Neuropathy Due to Vitamin B Deficiency and/or Diabetes Mellitus (2013)
Peripheral neuropathy is a common problem faced by a large number of patients. Its etiology is multifactorial. Most common causes would be megaloblastic anaemia and diabetes mellitus. To that end, researchers conducted a preliminary study, which was published in Indian Practitioner, in a series of patients with peripheral neuropathy due to vitamin B12 deficiency and / or diabetes mellitus
An open labeled clinical study was conducted in 30 patients presenting with peripheral neuropathy and suffering from either megaloblastic anaemia (vitamin B12 deficient) and/ or diabetes mellitus. Vitamin B12 levels in blood were estimated at baseline and during therapy. Vitamin K2-7 capsules (100 mcg / capsule, twice a day) were given orally for 8 weeks. Patients kept a regular record of the intensity of the symptoms during the baseline and throughout the study. Symptoms included tingling and numbness along with weakness, fatigue and cramps. The intensity of the symptoms was assessed on a Visual Analog Scale (VAS). Blood biochemical and organ function tests were studied at the baseline, at the fourth week and at the end of the eighth week.
Depending on the basal VAS score the patients were divided in a moderate group and a severe group. By the end of eight week, the VAS score in both the groups was reduced to 1-2. The intensity, specifically of tingling and numbness, was reduced to a much greater extent. It was of interest to observe that 10 out of 23 patients of Vitamin B12 deficiency group had residual neuropathic symptoms in-spite of adequate levels of Vitamin B12 following vitamin B12 administration. The residual neuropathic symptom score reduced following Vitamin K2-7 therapy. Vitamin K2-7 was well tolerated clinically and found to be safe as per the organ functions in all the patients. No adverse events were reported during the period of therapy.
The researchers concluded that this preliminary study has shown that vitamin K2-7 at a dose of 100 mcg twice a day for 8 weeks was well tolerated and safe with a therapeutic activity for the symptoms of peripheral neuropathy. However, the therapeutic efficacy needs to be evaluated further in a larger sample size, with a placebo-controlled, randomized, double- blind trial.
âWhile this was a short-term trial with a small subject base, the results are promising and noteworthy,â says Dr. Katarzyna Maresz, president of the International Science and Health Foundation.
Reference:
Kulkarni VK, Upase DP, Dound YA, Jadhav SS, Bhave AA, Mehta DS, Vaidya ADB. The effect of vitamin K2-7 in peripheral neuropathy due to Vitamin B12 deficiency and/or diabetes mellitus: A Preliminary Study. The Indian Practitioner. Vol. 66 No.10, October 2013.
Berberine
The effects of berberine on a murine model of multiple sclerosis and the SPHK1/S1P signaling pathway
Jiaming Luo et al. Biochem Biophys Res Commun. (2017).
Abstract
Berberine (BBR) has shown neuroprotective properties. The present study aims to investigate the effects of BBR on experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), and SphK1/S1P signaling, which plays a key role in MS. EAE was induced in mice, followed by treatment with BBR at 50, 100, or 300 mg/kg/d. Neurophysiological function was evaluated daily; inflammation, cell infiltration, and the severity of demyelination were also examined. The SphK1, SphK2, and S1P levels in the animals and primary astrocyte culture were measured. We found that treatment with BBR reduced the loss of neurophysiological function and the degree of demyelination. Moreover, BBR was associated with a decrease in SphK1 and S1P levels both in the animals and in culture. These results indicated that BBR suppresses demyelination and loss of neurophysiological function by inhibiting the SphK1/S1P signaling pathway. The use of BBR as a treatment of MS warrant further exploration.
Keywords: Astrocytes; BBR; Experimental autoimmune encephalomyelitis; Multiple sclerosis; Sphingosine kinase-1; Sphingosine-1-phosphate.
https://pubmed.ncbi.nlm.nih.gov/28655617/
Berberine is suppressing an interesting signalling pathway here:
Sphingosine Kinase 1 and Sphingosine-1-Phosphate Signaling in Colorectal Cancer (2017)
Abstract
Sphingosine kinase 1 (Sphk1) is a highly conserved lipid kinase that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P). Growing studies have demonstrated that Sphk1 is overexpressed in various types of solid cancers and can be induced by growth factors, cytokines, and carcinogens, leading to the increase of S1P production. Subsequently, the increased Sphk1/S1P facilitates cancer cell proliferation, mobility, angiogenesis, invasion, and metastasis. Therefore, Sphk1/S1P signaling plays oncogenic roles. This review summarizes the features of Sphk1/S1P signaling and their functions in colorectal cancer cell growth, tumorigenesis, and metastasis, as well as the possible underlying mechanisms.
Keywords: sphingosine kinase 1, sphingosine-1-phosphate, colorectal cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666791/#__ffn_sectitle
Full literature review:
Added 23rd June â22:
Quercetin
Quercetin reduces inflammation in a rat model of diabetic peripheral neuropathy by regulating the TLR4/MyD88/NF-ÎşB signalling pathway (2021)
Abstract
Neuroinflammation contributes significantly to the pathogenesis of diabetic peripheral neuropathy (DPN). Quercetin reportedly exerts neuroprotective effects in DPN. Here, we aimed to evaluate the potential anti-inflammatory effects of quercetin in a DPN rat model. Eight weeks after streptozotocin administration, diabetic rats were treated with quercetin (30 and 60 mg/kg/day orally) for 6 weeks. We assessed the mechanical withdrawal threshold (MWT), nerve conduction velocity (NCV) and morphological changes in sciatic nerves. Additionally, we measured the levels of tumour necrosis factor-alpha (TNF-ι), interleukin (IL)-1β, and IL-6 by ELISA and the expression of TLR4, MyD88, and NF-κB in sciatic nerves by western blotting and immunohistochemical assays. Our results revealed that blood glucose levels and body weight were unaltered following quercetin treatment. However, quercetin improved MWT (p < 0.05), NCV (p < 0.05), and pathological changes in the sciatic nerves of DPN rats. Quercetin significantly alleviated the increased expression of TNF-ι (p < 0.05) and IL-1β (p < 0.001). Furthermore, high-dose quercetin administration significantly downregulated the expression of TLR4 (p < 0.001), MyD88 (p < 0.001), and NF-κB (p < 0.001) in sciatic nerves of DPN rats. Our findings revealed that quercetin could reduce the levels of inflammatory factors in DPN rats, possibly mediated via the downregulation of the TLR4/MyD88/NF-κB signalling pathway. Collectively, these results suggest that although quercetin did not decreased blood glucose levels or reversed the reduced body weight, it showed anti-inflammatory and neuroprotective effects, which was beneficial for the treatment of DPN.
Keywords: Diabetic peripheral neuropathy; Inflammation; MyD88; NF-ÎşB; Quercetin; TLR4.
https://pubmed.ncbi.nlm.nih.gov/34743981/
Potential Implications of Quercetin in Autoimmune Diseases (2021)
Abstract
Autoimmune diseases are a worldwide health problem with growing rates of morbidity, and are characterized by breakdown and dysregulation of the immune system. Although their etiology and pathogenesis remain unclear, the application of dietary supplements is gradually increasing in patients with autoimmune diseases, mainly due to their positive effects, relatively safety, and low cost. Quercetin is a natural flavonoid that is widely present in fruits, herbs, and vegetables. It has been shown to have a wide range of beneficial effects and biological activities, including anti-inflammation, anti-oxidation, and neuroprotection. In several recent studies quercetin has reportedly attenuated rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and systemic lupus erythematosus in humans or animal models. This review summarizes the evidence for the pharmacological application of quercetin for autoimmune diseases, which supports the view that quercetin may be useful for their prevention and treatment.
Keywords: autoimmune diseases, quercetin, rheumatoid arthritis, inflammation, oxidative stress
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260830/
Neuropharmacological Effects of Quercetin: A Literature-Based Review (2021)
Abstract
Quercetin (QUR) is a natural bioactive flavonoid that has been lately very studied for its beneficial properties in many pathologies. Its neuroprotective effects have been demonstrated in many in vitro studies, as well as in vivo animal experiments and human trials. QUR protects the organism against neurotoxic chemicals and also can prevent the evolution and development of neuronal injury and neurodegeneration. The present work aimed to summarize the literature about the neuroprotective effect of QUR using known database sources. Besides, this review focuses on the assessment of the potential utilization of QUR as a complementary or alternative medicine for preventing and treating neurodegenerative diseases. An up-to-date search was conducted in PubMed, Science Direct and Google Scholar for published work dealing with the neuroprotective effects of QUR against neurotoxic chemicals or in neuronal injury, and in the treatment of neurodegenerative diseases. Findings suggest that QUR possess neuropharmacological protective effects in neurodegenerative brain disorders such as Alzheimerâs disease, Amyloid β peptide, Parkinsonâs disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. In summary, this review emphasizes the neuroprotective effects of QUR and its advantages in being used in complementary medicine for the prevention and treatment o of different neurodegenerative diseases.
Keywords: quercetin, neuropharmacological effects, neural damage, signaling pathways, mechanisms, neurodegenerative disorders
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248808/
Rutin
The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy (2013)
Background
Oxaliplatin, the third-generation platinum compound, has evolved as one of the most important therapeutic agents in colorectal cancer chemotherapy. The main limiting factor in oxaliplatin treatment is painful neuropathy that is difficult to treat. This side effect has been studied for several years, but its full mechanism is still inconclusive, and effective treatment does not exist. Data suggest that oxaliplatinâs initial neurotoxic effect is peripheral and oxidative stress-dependent. A spinal target is also suggested in its mechanism of action. The flavonoids rutin and quercetin have been described as cell-protecting agents because of their antioxidant, antinociceptive, and anti-inflammatory actions. We proposed a preventive effect of these agents on oxaliplatin-induced painful peripheral neuropathy based on their antioxidant properties.
Methods
Oxaliplatin (1 mg/kg, i.v.) was injected in male Swiss mice, twice a week (total of nine injections). The development of sensory alterations, such as thermal and mechanical allodynia, was evaluated using the tail immersion test in cold water (10°C) and the von Frey test. Rutin and quercetin (25-100 mg/kg, i.p.) were injected 30 min before each oxaliplatin injection. The animalsâ spinal cords were removed for histopathological and immunohistochemical evaluation and malondialdehyde assay.
Results
Oxaliplatin significantly increased thermal and mechanical nociceptive response, effects prevented by quercetin and rutin at all doses. Fos immunostaining in the dorsal horn of the spinal cord confirmed these results. The oxidative stress assays mainly showed that oxaliplatin induced peroxidation in the spinal cord and that rutin and quercetin decreased this effect. The flavonoids also decreased inducible nitric oxide synthase and nitrotyrosine immunostaining in the dorsal horn of the spinal cord. These results suggest that nitric oxide and peroxynitrite are also involved in the neurotoxic effect of oxaliplatin and that rutin and quercetin can inhibit their effect in the spinal cord. We also observed the preservation of dorsal horn structure using histopathological analyses.
Conclusions
Oxaliplatin induced painful peripheral neuropathy in mice, an effect that was prevented by rutin and quercetin. The mechanism of action of oxaliplatin appears to be, at least, partially oxidative stress-induced damage in dorsal horn neurons, with the involvement of lipid peroxidation and protein nitrosylation.
Keywords: Oxaliplatin, Oxidative stress, Pain, Flavonoids, Neuropathy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3835704/
Luteolin
Many of these plant derived flavonoids have similar efficacy.
Mast cell effects = allergies, which can exacerbate autoimmune conditions like MS or RA.
Treat the allergy as well and you again have a conduit to synergies.
Luteolin as a therapeutic option for multiple sclerosis (2009)
Abstract
Multiple sclerosis (MS) remains without an effective treatment in spite of intense research efforts. Interferon-beta (IFN-beta) reduces duration and severity of symptoms in many relapsing-remitting MS patients, but its mechanism of action is still not well understood. Moreover, IFN-beta and other available treatments must be given parenterally and have a variety of adverse effects. Certain naturally occurring flavonoids, such as luteolin, have anti-oxidant and anti-inflammatory effects, including inhibition of activated peripheral blood leukocytes from MS patients. Luteolin also inhibits mast cells, as well as mast cell-dependent T cell activation, recently implicated in MS pathogenesis. Moreover, luteolin and structurally similar flavonoids can inhibit experimental allergic allergic encephalomyelitis (EAE), an animal model of MS in rodents. An appropriate luteolin formulation that permits sufficient absorption and reduces its metabolism could be a useful adjuvant to IFN-beta for MS therapy.
https://pubmed.ncbi.nlm.nih.gov/19825165/
Bioavailability
You will see several therapeutics including silymarin (milk thistle) and quercetin referred to. We looked at piperine earlier. These are important as they greatly increase the bioavailability of many components of a therapeutic stack.
Silymarin is important not just for treating MS but tumours, epilepsy and so on.
Quercetin also improves bioavailability and efficacy of berberine:
% CDR = % cumulative drug release.
From Quercetin as Natural Bioavailability Modulator: An Overview (2020):
âŚIn conclusion, quercetin could be successfully utilized as bioenhancer to improve ex vivo permeability of berberine chloride, which would be expected to improve its bioavailability and reduce the dose resulting in improved patient compliance.
âŚincreased permeability of berberine chloride during pre-treatment study with quercetin might have resulted from the quercetin, which inhibited the efflux pump P-gp. Briefly, inhibition of efflux pump P-gp by quercetin might be duly responsible for permeability enhancement of berberine chloride.
âŚBased on these data, it could be suggested that 10 mg of quercetin for 30 minutes pretreatment time was optimum to increase the permeability of poorly permeable berberine chloride up to a maximum of 90.91% Âą 1.66% CDR.
P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review (2012)
Abstract
Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. P-glycoprotein (P-gp) is a member of the ATP-dependent membrane transport proteins; it is known to pump substrates out of cells in ATP-dependent mechanism. The over-expression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the cytotoxicity of a broad spectrum of antitumor drugs. Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes, vinca alkaloids, and podophyllotoxins. Besides several chemically synthesized P-gp inhibitors/blockers, some naturally occurring compounds and plant extracts were reported for their modulation of multidrug resistance; however, this review will focus only on major classes of naturally occurring inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293676/
Silymarin in Combination with Vitamin C, Vitamin E, Coenzyme Q10 and Selenomethionine to Improve Liver Enzymes and Blood Lipid Profile in NAFLD Patients (2020)
Abstract
Background and Objectives: Non-Alcoholic Fatty Liver Disease (NAFLD) is an emerging cause of hepatopathy that is showing an increasing trend and where the recommendations of lifestyle modification are often not sufficient. The aim of this study is to evaluate the efficacy and tolerability profile of the association of silymarin, vitamin C, vitamin E, coenzyme Q10 and selenomethionine (Medronys epatoÂŽ) by analyzing liver enzymes, along with the lipidic profile, as markers of liver function, and ultrasound results in NAFLD patients. Materials and Methods: This study enrolled 81 patients with mild to severe NAFLD, divided into two groups: Group A (N = 41) received two capsules a day of silymarin, vitamin C, vitamin E, coenzyme Q10 and selenomethionine (Medronys epatoÂŽ), and Group B (N = 40) received only recommendations for lifestyle modification including hypocaloric diet, physical exercise and encouragement for weight loss. Patients have been evaluated at three timepoints: baseline (T0), after 45 days of treatment (T1) and after 90 days of treatment (T2), by collecting blood parameters of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and the lipid blood profile. Ultrasonographic results have been analyzed at T0 and T2, along with the tolerability profile and side effects, registered at time T2. Results: The administration of the association of silymarin, vitamin C, vitamin E, coenzyme Q10 and selenomethionine (Medronys epatoÂŽ) was effective since it showed a significant reduction of the evaluated parameters of ALT, AST, ALP and GGT, a significant improvement of lipid parameters, evaluated as markers of liver function, and improvements of ultrasonographic results. The use of this formulation at the dosage of two capsules a day has been well tolerated and no adverse events have been reported during study period of three months. Conclusions: The administration of the association of silymarin, vitamin C, vitamin E, coenzyme Q10 and selenomethionine (Medronys epatoÂŽ) was effective and well tolerated in the improvement of hepatic function of NAFLD patients.
Keywords: coenzyme Q10; non-alcoholic fatty liver disease (NAFLD); selenomethionine; silymarin; vitamin C; vitamin E.
Coenzyme Q10 and Silymarin Reduce CCl4-Induced Oxidative Stress and Liver and Kidney Injury in Ovariectomized RatsâImplications for Protective Therapy in Chronic Liver and Kidney Diseases (2021)
Abstract
Oxidative stress is one of the key factors in the pathophysiology of liver disease. The present study aimed to evaluate the potential impact of two antioxidants, namely coenzyme Q10 (CoQ10) and silymarin, on carbon tetrachloride (CCl4)-induced oxidative stress and hepatic damage in ovariectomized rats. Female Long Evans rats were divided into six groups (n = 6): control, CCl4, CCl4 + CoQ10 (200 mg/kg), CCl4 + silymarin (140 mg/kg), Control + CoQ10, and Control + silymarin. Plasma and tissues from liver and kidney were analyzed for oxidative stress parameters and antioxidant enzyme activities using biochemical assays. Infiltration of inflammatory cells and fibrosis were assessed by histological staining of tissue sections. Both CoQ10 and silymarin significantly lowered serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels that were detected to be higher in CCl4 rats compared to controls. Significant reduction in CCl4-induced elevated levels of oxidative stress markers malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) was observed with both antioxidants. However, in control rats, CoQ10 and silymarin did not produce a significant effect. Histological analysis revealed that CCl4 markedly increased the level of inflammatory cells infiltration and fibrosis in liver and kidney tissues, but this was significantly reduced in CCl4 + CoQ10 and CCl4 + silymarin groups. Taken together, our results suggest that CoQ10 and silymarin can protect the liver against oxidative damage through improved antioxidant enzyme activities and reduced lipid peroxidation. Thus, supplementation of the aforementioned antioxidants may be useful as a therapeutic intervention to protect liver health in chronic liver diseases.
Keywords: coenzyme Q10, CCl4, silymarin, ovariectomized rat model, oxidative stress
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8830449/
Silymarin (milk thistle) for MS & PN
Immunoregulatory Effects of Silymarin on Proliferation and Activation of Th1 Cells Isolated from Newly Diagnosed and IFN-Ă 1b-Treated MS Patients (2019)
Abstract
Multiple sclerosis (MS) is a central nervous system autoimmune disease characterized by demyelination. Autoreactive T cells mainly interferon gamma (IFN-γ) producing T helper cells (Th1) have an important role in MS pathogenesis. Silymarin is a unique blend produced from milk thistle (Silybum marianum) plant which its imunomodulatory role has been indicated in studies. In the present study, the effects of silymarin on isolated Th1 cells were investigated in newly diagnosed MS patients and those who received betaferon. PBMCs were separated from newly diagnosed and IFN-β-treated MS patients. The Th1 cell isolation from PBMCs was performed using a human Th1 cell isolation kit. Th1 cells were cultured in the presence of silymarin (50, 100, and 150 ΟM for 48, 72, and 120 h). Th1 cell proliferation and CD69 expression were assessed by flow cytometry. Also, IFN-γ production and T-bet gene expression were measured by ELISA and real-time PCR respectively. In vitro cultured Th1 cells showed that silymarin suppresses Th1 cell proliferation dose and time dependently in newly diagnosed and IFN-β-treated MS patients in comparison to DMSO control. Also, CD69 expression as an early activation marker was changed after Th1 cell treatment with different doses of silymarin at different times. T-bet gene expression was significantly decreased in Th1 cells isolated from newly diagnosed and IFN-β-treated RRMS patients after treatment with silymarin compared to DMSO control. Additionally, IFN-γ production by Th1 cells was decreased after treatment silymarin in newly diagnosed patients; however, in IFN-β treated after 48-h treatment with silymarin, IFN-γ concentration was decreased at concentrations of 100 and 150 ΟM, and after 120 h, a significant increase was observed in the IFN-γ level at a concentration of 100 ΟM in comparison with DMSO. Our findings here clearly show that silymarin is an effective regulator for Th1 response in vitro condition. It not only suppresses Th1 proliferating activity but also inhibits T-bet gene expression and IFN-γ production by these cells.
Keywords: Th1 cells; immunoregulatory; interferon-β therapy; multiple sclerosis; silymarin
https://pubmed.ncbi.nlm.nih.gov/30178232/
Effects of silymarin on neuropathic pain and formalin-induced nociception in mice (2015)
Abstract
Objectives
Based on the previous reports, silymarin can suppress nitric oxide, prostaglandin E2 (PGE2), leukotrienes, cytokines production, and neutrophils infiltration. Regarding the fact that inflammation plays an important role in neuropathic and formalin-induced pain, it was assumed that silymarin could reduce pain. The present study investigates the analgesic effects of silymarin in chemical nociception and a model of neuropathic pain.
Materials and methods
Chemical nociception was produced by injection of 20 Âľl of formalin (0.5% formaldehyde in saline) into the plantar region of the right hind paw. A sciatic-nerve ligated mouse was applied as the model of neuropathic pain and the antinociceptive response of silymarin was examined 14 days after unilateral nerve-ligation using the hot plate test.
Results
The intraperitoneal administration of silymarin (25, 50, and, 100 mg/kg) 2 hr prior to the intraplantar formalin injection suppressed the nociceptive response during the late phase of the formalin test significantly, but it was not in a dose-dependent manner. Different doses of silymarin 14 days after unilateral sciatic nerve ligation in hot plate test did not induce obvious antinociception.
Conclusion
Results of the present study indicated that repeated administration of silymarin prevents the formalin-induced nociceptive behavior. However, it is not effective in the treatment of sciatic neuropathic pain.
Phase I
In 3 experiments, after interplanetary injection of formalin, neither diclofenac nor different doses of silymarin produced antinociceptive response as compared with control group (Figure 1A, â,B,B, â,C,C, phase I).
Phase II
Intraperitoneal administration of different doses of silymarin in three experiments inhibited paw licking completely similar to 15 mg/kg diclofenac in the second phase of formalin test (P<0.05) (Figure 1A, â,B,B, â,C,C, phase II). However, the difference among various doses of silymarin in three experiments was not significant. In experiment C, 25 mg/kg of silymarin failed to produce antinociceptive response (Figure 1C, phase II).
antinociception: the action or process of blocking the detection of a painful or injurious stimulus by sensory neurons.
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID)
We see similar efficacy to the NSAID in all 3 experiments and both phases, which is very encouraging to see and the largest effects after the first dose only, as per the above discussion by the authors.
Combined with curcumin, piperine and other therapeutics and you can see why synergism occurs.
Sciatica simulation (= no significant difference):
https://europepmc.org/article/PMC/PMC4556767
Other advice and precautions
Echinacea
Echinacea has a long history of treating medical conditions. It is a very popular and well-researched herb. Echinacea was used by North American Indians and, in the early 1900s, was the primary herbal treatment for infection. Despite the potential risk echinacea poses for those with MS, some popular books on alternative medicine specifically recommend echinacea for people with MS.
Echinacea may prevent or lessen the severity of viral infections. In some instances, viral infections lead to MS attacks and therefore prevention of these infections may produce benefits for people with MS. The work concerning echinacea and viral infections has produced mixed results, but some of this work does suggest echinacea may decrease their length and severity.
Echinacea may stimulate the immune system. Specifically it may stimulate T cells and macrophages, cells that are already overactive in MS. This stimulation may act in opposition to many of the conventional medications for MS, which work to depress immune system activity. It is also possible that echinacea could worsen MS.
Conventional methods, such as hand washing, flu vaccines, and newer prescription drugs, may be a safer and more effective way for people with MS to prevent and treat viral infections.
Echinacea may cause liver damage. This effect may be amplified by some conventional MS medications, known to be associated with liver injury. With the limited information available at this time, the safest course of action for people with MS is to avoid echinacea.
References and Additional Reading
Books
Bowling AC. Complementary and Alternative Medicine and Multiple Sclerosis. New York: Demos Medical Publishing, 2007.
Bowling AC, Stewart TS. Dietary Supplements and Multiple Sclerosis: A Health Professionalâs Guide. New York: Demos Medical Publishing, 2004.
Jellin JM, Batz F, Hitchens K, et al. Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Faculty, 2009.
Ulbricht CE, Basch EM, eds. Natural Standard Herb and Supplement Reference: Evidence-Based Clinical Reviews. St. Louis: Elsevier-Mosby, 2005.
http://neurologycare.net/echinacea.html
Full review:
Relieving Multiple Sclerosis Symptoms Naturally
Natural Treatments For Multiple Sclerosis
Choosing the best multiple sclerosis treatment depends on the symptoms experienced, and severity of the condition. You will need to determine which remedies work best for your situation. Herbal remedies for Multiple sclerosis include chamomile, St. John's wort, echinacea, and fish oil. Additional herbs that are used to relieve multiple sclerosis symptoms include echinacea, sage, and milk thistle. Due to possible side effects, and adverse interactions with other medications, it is important to consult a doctor before treating multiple sclerosis with herbal products.
Fish oil is believed to be helpful for people with multiple sclerosis. Symptoms that may be relieved with fish oil include muscle ache or pain, memory problems, and nerve inflammation. Echinacea may be helpful in the treatment of inflammation and pain associated with the symptoms of multiple sclerosis. Stomach upset, insomnia or sore throat may occur when using echinacea, especially for a long period of time. Sage and milk thistle are popular multiple sclerosis treatment options. Milk thistle is used to purify the blood and helps to improve the health of people with multiple sclerosis. Sage is used to aid digestion and is also believed to prevent spasms of the muscles.
Vitamin D supplementation is believed to be of benefit in treating multiple sclerosis. There seems to be an association between MS relapse rate and vitamin D levels. Perhaps increased sun exposure may be helpful in protecting against the risk of occurrence this condition.
There are a number of alternative and complementary therapies that can help to relieve the symptoms of this disease. These include massage, homeopathy, and acupuncture. It is important to make diet and lifestyle changes such as exercising regularly, eating a healthy diet and getting adequate rest in order to minimize the symptoms of multiple sclerosis.
Full article:
Added 19th July â22:
Citicoline
The Post-Covid Pharmacist recommends Citicoline as another treatment for neurological disorders:
it is very easy to find... just be sure to get Cognizin (brand), or may be labeled w generic name "citicholine"... i have also used "CDP-choline"... uridine is in the same pathway, so i have added uridine with success, low doses preferred (mine is 25 mg from Cardiovascular Research brand, also tried 85 mg in the past)... may cause headaches if you don't start Cognizin at 250 mg fwiw... but it has been amazing from my experience and anecdotes at the Rx since '19âŚ
https://substack.com/profile/70122106-the-post-covid-pharmacist
Citicoline: A Candidate for Adjunct Treatment of Multiple Sclerosis, (2021)
Abstract
In remittingârelapsing multiple sclerosis (RR-MS), relapses are driven by autoreactive immune cells that enter the brain and spinal cord and damage myelin sheaths of axons in white and grey matter, whereas during remissions myelin is repaired by activated oligodendroglial cells. Disease-modifying therapies (DMTs) may either retard/attenuate myelin damage or promote/enhance/speed up myelin repair. Almost all currently approved DMTs inhibit myelin damage and are considerably toxic. Enhancement of myelin repair is considered an unmet medical need of MS patients. Citicoline, known for many years as a nootropic and neuroprotective drug and recently pronounced food supplement, has been found to be significantly efficacious in two complementary rodent models of MS, experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced myelin toxicity. Moreover, citicoline treatment improves visual evoked potentials (VEPs) in glaucoma patients, which is relevant because VEP monitoring is frequently used as an indicator of remyelination in MS. Although over-the-counter availability of citicoline may impede its formal translation to the clinic of MS, evaluation of its efficacy for supporting remyelination in this disease is strongly indicated.
Keywords: citicoline, multiple sclerosis, demyelination, remyelination
We conclude that citicoline certainly deserves attention as a food substance that, when added to the current treatment regime of RR-MS, may enhance and accelerate remyelination. Its possible benefit for patients suffering from progressive forms of MS may also deserve evaluation.
Full paper:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066453/
Added 17th November â22:
Chinese Skullcap (Scutellaria baicalensis) and Baicalin
Therapeutic properties of Baicalin
A literature review
Abstract
This Substack is a scientific literature review of much of the current research into the therapeutic benefits and mode of action of baicalin and its associated flavonoids.
Zhao et al (2019) published a systematic and comprehensive overview on the traditional usages, botany, phytochemistry, pharmacology, pharmacokinetics and toxicology of Scutellaria baicalensis Georgi.
The Ukranians have known for at least 12 years that Baicalin (among other flavonoids) has furin inhibitory effects. Translated from Russian, a paper by Kibirev et al from back in 2010 is reviewed.
Four years later and in 2016 the Palladin Institute published an updated paper on the latest research into furin inhibitors, their structure and efficiency.
Nhoek et al investigated flavonoids from Scutellaria baicalensis and their inhibitory activity against PCSK9 expression in a paper from 2018.
In 2016 Bao et al conducted in vivo studies and found a strong correlation between SREBP-1 levels and breast cancer tumor differentiation and metastasis.
Mahboobnia et al performed a literature review of the pathology linked to PCSK9 in 2021. In contrast to suppressing apoptosis, PCSK9 appears to promote apoptosis of nerve cells in the cerebellum.
In 2016, Moore et al published a paper on how to optimise the extraction efficiency of baicalin, its anticancer effects, bioavailability and nanotechnology.
They found that ultrasound-assisted extraction (UAE), which uses cavitation, is an efficient way to extract the compound using a solvent of 40% ethanol at 60°C, and combing this technique with heat reflux extraction (HRE) increase the yield and efficiency further still.
They then described modes of action at inhibiting cancer cells, which is promising as an alternative to the very common side effects of radiotherapy and chemotherapy.
In 2017, Lin et al summarised which natural compounds from herbs can induce autophagy in cancer cells.
Shen et al (2013) describe how TRAF2 is an NF-ÎşB-activating oncogene in epithelial cancers, which is why induced degradation by baicalin can provide us with another anti-cancer signalling pathway.
Hua et al (2019) describe RelB/p52 associated autophagy in detail, with reference to cervical cancer.
Some miRNAs have oncogenic or tumor suppressive properties. In 2021 Ge et al performed in vitro based microarray analysis of the effects of baicalin on miRNAs involved with breast cancer, which is another of the signalling pathways that it uses to inhibit tumorigenesis.
2016, and Liu et al conducted a review of research into the effects of baicalein on different cancer types and the possible mechanisms involved. The abstract and diagram alone are extremely informative.
In 2000, Chan et al conducted an in vitro study into the effects of baicalin on several prostate cancer cell lines. They found that the responses to baicalin were different among different cell lines, and that 50% inhibition of DU145 cells (considered a standard prostate cancer cell line) occurred at concentrations of 150Îźmol or above. LNCaP cells were the most resistant (androgen-sensitive human prostate adenocarcinoma cells).
Xu et al (2018) conducted in vitro and in vivo investigations into the hepatoprotective effects of silybin when co-administered with baicalein, using rats as a model. They found that baicalein improved the oral bioavailability of silybin with enhanced liver protective effects, inhibition of breast cancer resistance protein (BCRP) and suppression of multidrug resistance protein 2 (MRP2).
In 2000, Li et al performed an in vitro investigation into how baicalin flavonoids can inhibit HIV-1 infection at the level of viral entry.
They used 96-well tissue culture plates in the presence or absence of BA (Baicalin, 7-glucuronic acid,5,6-dihydroxyflavone) at designated concentrations, and repeated the experiments at least 3 times before analysing the group data using a Studentâs t test, and found that baicalin can inhibit viral entry and replication, but not block binding to CD4 T-cells via glycoprotein 120 (gp120).
It has been confirmed by replicable BLAST analysis that the spike protein trimer includes HIV inserts homologous with gp41 and the cytotoxic & neurotoxic glycoprotein 120 (gp120).
It is also known that spike S1 has binding affinity for neuropilin 1 (Nrp1) receptors and nicotinic acetylcholine receptors, thus providing mechanisms to facilitate endocytosis into several cell types including neurons, much as the HIV virus does.
A paper by Lee et al also makes the connection between gp120 and amyloidosis via signalling pathways including iNOS and COX-2. All this is of potential relevance to the diagnosis and treatment of the condition and as COX-2 is linked to tumorigenesis and amyloidosis is linked to Alzheimer's disease, although cause and effect is controversial. Baicalin demonstrates neuroprotective properties, including by targeting the above iNOS and COX-2 inflammatory signalling pathways. Woo et al conducted an in vitro investigation (2006) and found that it mediates this by inhibiting COX-2 gene expression.
Alvarez et al (2007) also conducted an in vitro study of gp120 and found that it induces COX-2 promoter transcription through NF-kappaB activation in astrocytoma cells.
In 2015, Noh et al were studying the effects of baicalin on oral pharmacokinetics of caffeine in rats, specifically for interactions with CYP3A4 activity as marked by ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), benzyloxyresorufin O-debenzylase (BROD) and p-nitrophenol hydroxylase and erythromycin N-demethylase.
Baicalin was suspended in corn oil and fed to the rats with oral baicalin reaching its maximum concentration in plasma 8 hr after administration. Plasma concentration was then determined and found to be well below the concentrations used in a previous study. Plasma concentrations were in fact very low because it is converted quickly to other metabolites, meaning that certain CYP drug interactions would not be contraindicative.
A study by Yu et al in 2022 found that baicalin attenuates amyloid β oligomers induced memory deficits and mitochondria fragmentation through regulation of PDE-PKA-Drp1 signalling.
Parkinsonâs disease. In 2019 Tu et al used a compound called 6-OHDA to induce the disease in rats. 6-hydroxydopamine is a kind of nerve agent that induces lesions in the brain, the resulting loss of dopamine produces Parkinsonâs like symptoms which can be used as control against rats also administered baicalin.
They concluded that baicalin has significant protective effect on 6-OHDA-induced PD rats, which may play a protective role through an antioxidant, promoting the release of neurotransmitters and regulating the metabolism of N-acetyl aspartate and glutamate.
In 2012, Lu et al used mice bearing pancreatic tumor grafts which had been fed a baicalin supplemented diet. They found that some of the baicalin gets methylated to oroxylin A (OA) and its conjugates in various organs during absorption, and some of these have anti-tumor properties. In fact the anti-tumor effects in this study were so pronounced that âonly 3 out of 6 mice treated with SB extract grew tumors large enough to be analyzedâ. This study showed that baicalin or related metabolites may accumulate in plasma, tumor xenografts, and pancreas, liver, lung, and other tissues in vivo.
A paper by Ha et al (2012) is paywalled but also found that the breakdown product of baicalin, oroxylin A (OA) inhibits COX-2 as well as decreasing PGE2 levels in HT-29 human colon cancer cells.
In addition to the above, research by Chen, Yang & Lee (2000) added to our knowledge about the effects of oroxylin A.
Regarding antiviral properties, a patent was filed in 2009 for Baicalin as a treatment for SARS infection.
And in 2020 Su et al published a preprint of their research findings from investigating the protease inhibition of SARS-CoV-2 by baicalin and baicalein. The cell-based antiviral activity of baicalin or baicalein is superior to most of the reported compounds and that of baicalein is close to those of chloroquine (EC50: 1.13 ÎźM; SI > 88) and remdesivir (EC50: 0.77 ÎźM; SI > 129).
Shuanghuanglian (Chinese: ĺéťčż), a traditional Chinese medicine and its uses and pharmacology are then discussed.
In 2021, Ni et al published their findings from a randomized clinical trial of the effects of Shuanghuanglian against COVID-19.
They found that although the time to disease recovery was not reduced the viral load was significantly lower and pneumonia associated inflammation was significantly reduced. They do suggest that time to recovery may have been skewed due to patient transfers and waiting times before being randomly selected for trial.
In 2018 Bhattacharjee & Dey published a literature review discussing phytomelatonin or plant based sources of melatonin, and S. baicalensis is a source of the hormone.
At up to 7Âľg/g S. baicalensis is not a rich source of melatonin but it is worth considering as 3 grams/day could be enough to reach the physiological dose threshold for some people and synergism tends to amplify any effects.
In 1994 Zaidan et al found that only 20 micrograms was enough to have an effect.
In 2017 Jin, Huang and Zhu collected tissue samples from 6 female patients with endometriosis, cultured the endometrial stromal cells and exposed some of them to baicalein, with control cells for comparison. They found that baicalein may suppress the viability of human endometrial stromal cells through the NF-ÎşB signaling pathway in vitro, and may induce apoptosis and promote cell cycle arrest at the G0/G1 phase. Thus, baicalein may provide a novel treatment option for endometriosis.
Liang et al (2019) induced ulcerative colitis (UC) in rats and treated it using baicalin, baicalein, or a combination of the two. They found that the high baicalin content of YSR (Young Scutellaria baicalensis ratio of baicalin and baicalein) exhibited the best treatment effects.
Treatment of ME/Chronic Fatigue Syndrome (CFS). Various sufferers of the syndrome have reported increased energy levels after taking extracts of S. baicalensis, which was attributed to baicalin.
In 2019 Ishfaq et al investigated the antagonistic effects of baicalin on infected chicken lungs by the restoration of energy metabolism and found a significant improvement.
Zhang et al (2015) found that baicalin has significant potential as an anti-inflammatory agent for the treatment of autoimmune diseases such as multiple sclerosis (MS) by preventing Th1 and Th17 cell differentiation via the STAT/NFÎşB signalling pathway.
Building on previous research, in 2018 another team of Chinese researchers, Xu et al, used dextran sodium sulfate (DSS) to induce colitis in mice and found that baicalein and baicalin downregulated STAT4 transcription in colon epithelial cells, thus exhibiting therapeutic effects on autoimmune diseases by regulating cell proliferation.
Moving on to 2021, and Wang et al reported on how baicalin protects the blood-brain barrier from injury mediated by lipopolysaccharide (LPS) using a mouse model.
Of particular interest for the treatment of demyelinating diseases like MS or peripheral neuropathy, in 2022 Ai et al found that, using a neonatal mouse model, baicalin promotes myelin production and regeneration by activating the PPARÎł signal pathway and also confirmed that BA is an effective natural product for the treatment of demyelinating diseases.
In our final paper on autoimmunity, also from 2022, Wang et al conducted a literature review of Scutellaria baicalensis georgi as a promising candidate for the treatment of autoimmune diseases.
Dosing, contraindications and administration in a clinical setting are then considered to conclude the review.
Full review:
Icariin
From the forthcoming full review:
Icariin ameliorates the progression of experimental autoimmune encephalomyelitis by down-regulating the major inflammatory signal pathways in a mouse relapse-remission model of multiple sclerosis (2020)
Abstract
This study aimed at investigating whether treatment with icariin (ICA) could modulate the progression of experimental autoimmune encephalomyelitis (EAE) and its potential mechanisms in SJL/J mice. Female SJL/J mice were immunized with PLP139-151 peptide to induce relapse-remitting EAE and the immunized mice were treated with vehicle alone (EAE) or ICA (12.5 or 25 mg/body weights) by gavage daily for 42 days. Compared with the control, the EAE mice developed relapse-remitting EAE and reduced body weights (15.76 ¹ 0.61 vs. 17.60 ¹ 0.98 g on day 13; 17.35 ¹ 0.44 vs. 18.46 ¹ 0.66 g on day 26), accompanied by severe inflammation with many microglia infiltrates and obvious demyelination in the spinal cord tissues. Conversely, ICA treatment significantly reduced the clinical scores (on day 13, 1.00 ¹ 0.16 and 1.10 ¹ 0.33 for ICA 12.5 and 25 mg/kg group, respectively vs. 1.62 ¹ 0.41 in the EAE group; on day 26, 0.50 ¹ 0.23 and 0.40 ¹ 0.24 for ICA 12.5 and 25 mg/kg group, respectively, vs. 1.56 ¹ 0.29 in the EAE group), mitigated the body weight reduction, spinal cord inflammation and demyelination in EAE mice (pathological scores of 2.33 ¹ 0.82 and 1.11 ¹ 0.57 for ICA 12.5 and 25 mg/kg, respectively; vs. 4.78 ¹ 1.13, P < 0.0001). Furthermore, ICA treatment significantly mitigated the EAE-increased iNOS, TNF-ι, CD206 and TGF-β1, but further reduced IL-10 mRNA transcripts in the brain mice. More importantly, ICA treatment significantly mitigated the inflammation-related NF-κB, AKT, ERK1/2, p38, c-Jun and MEK phosphorylation in the brain of EAE mice. ICA treatment ameliorates the progression of EAE by down-regulating the major inflammation-related signal pathways in mice.
Keywords: Experimental autoimmune encephalomyelitis; Icariin; Microglia; Signaling.
5. Conclusions
In summary, our data indicated that ICA treatment minimized clinical scores and body weight reduction, and decreased inflammation and demyelination, accompanied by decreasing microglia activation and down-regulating the activation of multiple signal pathways in the CNS of EAE mice. Such novel findings suggest that ICA may be valuable for control of EAE process and may uncover the pharmacological action of ICA in inhibiting inflammatory diseases.
https://pubmed.ncbi.nlm.nih.gov/32871176/
Epimedium extract promotes peripheral nerve regeneration in rats (2013)
Abstract
Effects of Epimedium extract and its constituent icariin on peripheral nerve repair were investigated in a crush injury rat model. Animals were divided into four groups: sham, control, Epimedium extract, and icariin groups. At postoperative weeks 1, 2, 4, and 8, nerve regeneration and functional recovery were evaluated by sciatic functional index (SFI), nerve electrophysiology, nerve pinch test, and muscle wet weight. Results showed that at 2 and 4 weeks after surgery rats in the Epimedium group displayed a better recovery of nerve function than that in the icariin and control groups, with better recovery in the icariin group than in the control group. The nerve pinch test showed that nerve regeneration was greater in the Epimedium group and the icariin group as compared to the control group. In addition, the muscle wet weight in the Epimedium group was significantly improved when compared with the icariin group, and the improvement in the icariin group was better than that in the control group at 8 weeks after operation. Our findings suggest that Epimedium extract effectively promotes peripheral nerve regeneration and improves the function of damaged nerves.
Results demonstrated that Epimedium extract accelerated axonal growth, which is helpful to explain why the SFI in the Epimedium group was significantly improved at 2 and 4 weeks after operation as compared to the control group. Findings in nerve electrophysiological measurement, muscle wet weight measurement, and histological staining also supported that both Epimedium extract and icariin can exert protective effects on the motor function recovery and conductivity recovery in rats. It is presumed that icariin alone is effective to promote nerve regeneration, and may be one of the major components of Epimedium extract promoting the regeneration of peripheral nerves. However, the effects of Epimedium extract and icariin on the peripheral nerve regeneration are different, suggesting that components other than icariin in Epimedium extract may also facilitate the regeneration of peripheral nerves or coordinate this growth.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789416/
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I have an additional thought - oxygen - hypoxia is a causal factor in the finger pain of LongCovid. I had to figure that one out for myself in 2020 when I went off my medical marijuana to travel. Suddenly finger tingling and then pain were problems. Low magnesium was part of it but I was making my genetic imbalance/lack of endocannabinoid issue worse by still using CBD drops without any THC. Something about that was making the problem even worse. I stopped the CBD drops and increased magnesium as my temporary while traveling solutions. The problem mostly went away when I got back to medical marijuana state. See this post for the references I found, if interested. Motion - 'jazz hands' was part of my therapy strategies to increase oxygen to the extremities and to try to not white-knuckle drive in bad traffic. I realized that was part of the issue - bruising like pain from my own tension, but made worse by multiple deficiencies. Methyl B12 was probably a need too. I do use it but tend to forget my supplements. https://open.substack.com/pub/denutrients/p/cannabinoids-blood-vessels-and-longcovid?r=os7nw&utm_campaign=post&utm_medium=web
Wonderful write up. So much information here that Iâd need a lifetime to have found most of it (for my fatherâs rapid onset cognitive problems and sometimes severe myoclonus that I believe may be vaccine relatedâŚ). I am immensely grateful for your work and putting it all together in one piece. Thank you.