Alternative Approaches to Remyelination in Multiple Sclerosis by Eric Muradov, ND
Abstract
There are no currently approved remyelination therapies for Multiple Sclerosis (MS). However, understanding the composition of myelin, nutritional contributors towards myelination as well as non nutritional alternative approaches may aid those in need while other methods are developed. Fatty acids, vitamins and minerals are needed at different points in the biochemistry of myelination. Furthermore, repurposed medications, peptides, lifestyle interventions and amino acids also may be of benefit. Lastly, it appears that a synergistic approach may be more effective than pharmacologic dosing of individual nutrients.
Background
Multiple sclerosis (MS) is typically a relapsing, inflammatory condition of the central nervous system (CNS) (Tryfonos et al 2019). In Relapsing Remitting MS (RRMS) lymphocytic infiltration of the brain and spinal cord dominates early on, causing demyelination (Baldassari and Fox 2018). Oligodendrocytes are involved in the formation of myelin in the CNS (Dietz et al 2016). Oligodendrocytes also provide nutrition to the axons, fuelling axonal mitochondria, and support energy-demanding axonal transmission (Lubetzki et al 2020). Understandably, oligodendrocytes require two to three times more energy other brain cell types (Weiser et al 2016). Oligodendroglial loss and axonal injury also occurs as result of the lymphocytic processes (Kremer et al 2019). Local processes within the CNS are also thought to drive the disease which include localized inflammation driven by microglia and B-cells and resulting neurodegeneration, particularly in progressive MS (Faissner et al 2019).
The myelin sheath is interrupted by nodes of Ranvier so the action potential jumps from one node to the next (saltatory conduction) which allows rapid transmission of the action potential along the axon which is up to 100 times faster than unmyelinated axons (Monje 2018). The loss of myelin therefore leads to slower transmission of the action potential and contributes to the focal neurological clinical abnormalities common to the disease. The oligodendroglial loss leads to a loss of axonal nutritional support for ATP production contributing to eventual axonal loss (Cunniffe and Coles 2021). Demyelination increases the number of Na+ channels along the length of the axon which elevates the energy demands on the axon (increased Na+/K+ ATPase activity for axonal polarization, which in turn is needed for transmission of action potentials). If the energy demands are insufficiently met, the axonal Na+ gradient diminishes and the Na+/Ca2+ exchanger reverses and causes toxic levels of Ca+ in the axon and axonal degeneration ensues (Friese et al 2014). Therefore, remyelination is important not only to improve neuronal function and therefore clinical symptoms but also to prevent subsequent axonal loss and resultant neurodegeneration.
While spontaneous remyelination can occur, it is often incomplete. Remyelination is variable with some patients having extensive remyelination while others have almost no evidence of neuronal repair (Wooliscroft et al 2019). Myelin repair in the adult CNS appears to depend on pre-existing mature oligodendrocytes (Yeung et al 2014). Oligodendrocytes in the adult CNS are post-mitotic and are unable to proliferate and replace damaged oligodendrocytes (Zhang et al 2016). Pre-existing mature oligodendrocytes are able to increase their neuronal internodes and therefore contribute to recovery after demyelination (Duncan et al 2018). Experimental models in particular have established that after demyelination, new myelin can be synthesised by newly formed oligodendrocytes generated from oligodendrocyte precursor cells (OPCs) or neural stem cells (Lubetzki et al 2020). Rate of oligodendrocyte production decreases after five years of age and subsequently occurs at low levels. Remyelination is greatest in people aged less than 55 years and within the first 10 years of disease onset (Plemel et al 2017). Impaired recruitment of OPCs into a lesion and inability to differentiate into mature remyelinating oligodendrocytes are two main factors contributing to remyelination failure, with the latter a strong area of focus with regards to regenerative myelination approaches (Dulamea 2017). One study found that 20% of patients with MS repaired plaques efficiently (between 60% and 96% remyelinated) (Patrikios et al 2006). Optimistically, this suggests that close to full myelination is possible and perhaps there are modifiable factors that contribute towards it. This paper will explore lifestyle, hormonal and nutritional contributors in addition to easily accessible nutraceuticals and medications to potentially encourage the process.
Myelin composition: Myelin consists of 40 or more tightly wrapped lipid bilayers, and is 70-85% lipid and 15-30% protein in composition (Poitelon et al 2020). Structural proteins inside of myelin include Proteolipid Protein which accounts for over half the total protein in CNS myelin and Myelin Basic Protein that accounts for about 30% of the total in CNS myelin. A final major myelin protein is Myelin-Oligodendrocyte Glycoprotein, which is specific for the CNS and is selectively localized on the outside surface of myelin sheaths and oligodendrocytes and is susceptible to autoimmune attack (Quarles 2005).
The three classes of membrane lipids are cholesterol, phospholipids and glycolipids in a ratio of 40%:40%:20% respectively (Poitelon et al 2020). The brain contains about 20% of the body’s cholesterol, and due to the blood–brain barrier (BBB) the cholesterol present in myelin mostly comes from de novo synthesis in oligodendrocytes (Dietschy and Turley 2004).
In terms of glycolipids, the two sphingosine-containing glycolipids, the glycosphingolipids-galactosylceramide (cerebroside) and sulfatide (the sulfated form) are the most common lipids in myelin. Through transfer of sugar moieties to ceramide, galactosylceramide and glucosylceramide are generated, which can be further transformed into ganglioside and sulfatide, and are required for the stability and maintenance of myelin into old age (Schmitt et al 2015). Sphingomyelin is a phospholipid that is another major myelin component with a sphingosine backbone also produced from ceramide.
Plasmalogens are phospholipids, and are the next most abundant lipids present as phosphatidylcholine (PC) and mostly phosphatidylethanolamine (PE) species (a choline or ethanolamine head group) which can then produce phosphatidylserine. Phosphatidylcholine and ceramide are precursors for the synthesis of sphingomyelin (Denisova and Booth 2005, Vos et al 1997). In the sn-1 and sn-2 positions of their glycerol backbone, plasmalogens contain a fatty acyl chains, which is usually a polyunsaturated fatty acid, typically docosahexaenoic acid (DHA) in the sn-2, and a saturated fatty acid, typically arachidonic acid (AA) in the sn-1 position (Manni et al 2018, Paul et al 2019).
Oligodendrocytes require access to large quantities of lipids to myelinate multiple axons but to what extent this demand is supported by endogenous synthesis or lipid uptake is not fully understood (Dimas et al 2019). The brain is capable of synthesizing only a few nonessential fatty acids, therefore both essential fatty acids and even some nonessential fatty acids must enter the brain from the blood as free fatty acids through the blood brain barrier (Mitchell and Hatch 2011).
Nutritional Approaches
Humans can synthesize saturated and monounsaturated fatty acids, but they are not able to synthesize the n-3 fatty acid alpha-linolenic acid (ALA) and the n-6 fatty acid linoleic acid (LA) (Janssen and Kiliaan 2014). Downstream of ALA, quantitatively DHA (22:6n-3) makes up over 90% of the n-3 polyunsaturated fatty acids (PUFAs) in the brain as both eicosapentaenoic acid (EPA; 20:5n-3) and alpha-linolenic acid (ALA; 18:3n-3) are in the brain in only very small quantities. EPA conversion is not a significant source of DHA (Weiser et al 2016). It is well known that EPA and DHA can help control the magnitude and duration of inflammation by modulating innate and adaptive immune responses, thought of as “the fire fighters that extinguish inflammation” (Zahoor and Giri 2021). Beyond the 3-series of prostaglandins, and the 5-series of leukotrienes, EPA converts to specialized pro-resolving mediators (SPMs) namely the E-series resolvins and DHA to the D-series resolvins, protectins (known as neuroprotectins in neural tissues), and maresin SPMs (Duvall and Levy 2016). Also, n-3 PUFAs can help shift microglial polarization toward the beneficial M2 phenotype both in vitro and in vivo (Chen et al 2014). Clearly, beyond regulating inflammation, n-3 PUFAs have potential with regards to myelination because of their role in the structure of myelin phospholipids. Furthermore, DHA promotes oligodendrocyte progenitor maturation and counteracts the maturational arrest induced by TNF-α (Bernardo et al 2017). DHA has been shown to induce BDNF (brain-derived neurotrophic factor) expression both in vivo and in vitro (Sun et al 2018). BDNF is a neurotrophin and studies have demonstrated that mature oligodendrocytes are responsive to BDNF activity and BDNF directly promotes myelination through its effects on oligodendrocytes (Khorshid Ahmad et al 2016).
With regard to human data, one trial with fifty RRMS patients were administered 4 g/day of fish oil (0.8 g EPA, 1.6 g DHA total) for 12 months versus placebo. Fish oil decreased the serum levels of TNFα, IL-1β, IL-6, and nitric oxide metabolites compared with placebo group, however there was no difference in expanded disability status scale (EDSS), that is, a DHA dominant fish oil preparation did not improve disability as a standalone treatment, nor did it affect the annualized relapses rate (Ramirez-Ramirez et al 2013).
Comparatively, however, a one-year long double-blind trial where a “Fish Oil” group received 1.98g EPA and 1.32g DHA and a low-fat diet (15% fat) and an “Olive Oil” group received olive oil with the American Heart Association (AHA) Step I diet (30% fat). Outcomes demonstrated a trend towards an increase (worsening) in EDSS (+0.35 EDSS points) in the olive oil group vs. a modest decrease in EDSS (-0.07) in the Fish Oil group (Weinstock-Guttman et al 2005). This suggests that possibly the dose in Ramirez-Ramirez and colleagues (2013) was too low and/or the effect of the fish oil was potentiated by the low-fat diet. Similarly, sixteen newly diagnosed MS patients given fish oil (0.4g EPA and 0.5g DHA), low saturated fat intake recommendations and a low dose B Complex had a significant reduction in annual exacerbation rate and EDSS
(-0.54) (Nordvik et al 2000). These findings suggest that modifying dietary fat sources with consideration of the addition of B Vitamins can improve the EDSS, possibly through enhancing myelination. This was done in newly diagnosed MS patients which may also have a greater propensity for repair when less damage is present.
Thiamine (B1), as thiamin pyrophosphate, is a cofactor for the pyruvate dehydrogenase complex, used to convert pyruvate to acetyl-CoA, for use in the Krebs Cycle and therefore can help with neuronal energetics (Kerns and Gutierrez 2017). Thiamine is thought to participate in myelin production as deficiency in rats dramatically reduces brain cerebroside content, which as discussed, is a major component of myelin (Trostler et al 1977). Interestingly, beyond its use for myelination, strong data supports the use of B1 for MS fatigue where 600–1500mg/day orally (dose adjusted for body weight) or 100mg once a week parenterally (in patients larger than 80kg to reduce pill count) was found to improve the Fatigue Severity Scale an average of 41% (Costantini et al 2013). Oral Sulbutiamine (synthetic lipophilic B1) at 400mg has also been studied with positive effects on MS fatigue when taken for two months (Sevim et al 2017).
Riboflavin (B2) is involved in myelin formation in nerve cells, and it is a precursor to Flavin Adenine Dinucleotide (FAD). Riboflavin deficiency is thought to result in impaired brain lipid metabolism as a reduction in the proportion of myelin lipids (such as sphingomyelin, and phosphatidylethanolamine) has been reported in riboflavin-deficient rats (Ogunleye and Odutuga 1989). However, modest riboflavin supplementation (10mg) daily for six months did not alter EDSS scores in RRMS (Naghashpour et al 2013). The dosing in the study was possibly too conservative, for example, in the area of migraine prophylaxis, riboflavin dosing is often 400mg daily (Marashly and Bohlega 2017). Mechanistically, because riboflavin should improve neuronal energetics via FAD, and has a role to play in myelination, supplementary incorporation is suggested.
Vitamin B3 occurs naturally in two forms: niacin (also called nicotinic acid) and niacinamide/nicotinamide (Gasperi et al 2019). Some preliminary data exists supporting niacinamide in preventing axonal degeneration, likely through increased NAD+ levels (Kaneko et al 2006). Niacin has been recently found to upregulate CD36 expression and myelin debris clearance in lesions by macrophages and microglia which is then accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in demyelinated mice. Myelin debris contains inhibitors of OPC differentiation and so its clearance, by phagocytosis, is an important step in the regeneration of the myelin sheath (Robinson and Miller 1999). Niacin dosing has not been studied in MS per se, but some older data suggests that the use of high dose oral Niacin (100mg to 3000mg) with other nutrients may be helpful for reversing symptoms in MS (Klenner 1973).
Pantothenic Acid (B5), the precursor of CoA, is an indispensable cofactor especially in the Krebs Cycle (Kelly 2011). CoA plays specialized roles in the brain as Acetyl-CoA Carboxylase (ACC) catalyzes the first committed step in fatty acid biosynthesis which converts acetyl-CoA to malonyl-CoA where it mediates the synthesis of the complex fatty-acyl chains of glycosphingolipids and phospholipids (Ismail et al 2020, Manni et al 2018, Tansey and Cammer 1988). CoA is also needed for cholesterol synthesis beginning with the condensation of two acetyl-CoA molecules to form acetoacetyl-CoA (Cerqueira et al 2016, Czumaj et al 2020). Although B5 has not been specifically studied in MS, its role in cholesterol, glycolipid and phospholipid synthesis implies its appreciable inclusion into the diet of an MS patient.
Vitamin B6, in its coenzyme form, pyridoxal 5′‐phosphate serves as a cofactor in sphingolipid synthesis and is thereby important for myelin formation. Pyridoxal phosphate is a cofactor for serine palmitoyltransferase (Denisova and Booth 2005). All sphingolipids share a defining structural component called a long-chain base which are formed by serine palmitoyltransferase in the first and rate-limiting step of sphingolipid de novo synthesis (Lone et al 2020). Furthermore, because synthesis of neurotransmitters like dopamine, serotonin and gamma‐aminobutyric acid (GABA) from glutamate depends on pyridoxine, it is also thought to be related to general health of the nervous system and modulating glutamate excitotoxicity (Calderón-Ospina and Nava-Mesa 2020).
Folate (B9) is a generic term for a family of compounds which includes and principally refers to the metabolically active 5-methyltetrahydrofolate (5-MTHF). 5-MTHF is the most abundant form found in plasma, representing more than 90% of folate (Scaglione and Panzavolta 2014). Folate enhances oligodendrocyte maturation both in vitro and in vivo, related to oligodendrocyte-specific dihydrofolate reductase (DHFR) expression as pharmacological inhibition of DHFR causes severe defects in oligodendrocyte survival (Weng et al 2017).
Cobalamin (B12) refers primarily to its principal coenzyme forms Adenosylcobalamin and Methylcobalamin which are for mitochondrial and methylation functions, respectively, both of which impact myelin synthesis (Smith et al 2018). The neurologic manifestations of cobalamin deficiency begin with demyelination, followed by axonal degeneration and eventual irreversible damage due to axonal death in both the CNS and peripheral nervous system (Miller et al 2005). Adenosylcobalamin is required for Krebs cycle conversion of methylmalonyl-CoA (which is produced from propionyl-CoA) to succinyl-CoA by methylmalonyl-CoA mutase (Froese et al 2019). Cobalamin deficiency results in accumulation of propionyl-CoA which is the launching point for odd-chain fatty acid synthesis, therefore, large amounts of odd-chain (C15 and C17) fatty acids are produced and incorporated into the nerve sheaths, which results in altered, abnormal myelin (Dror and Allen 2008, Metz 1992, Park et al 2020). Methylcobalamin is involved in the conversion of homocysteine to methionine (coenzyme for methionine synthase) which is subsequently converted into S-adenosylmethionine (SAMe) (Froese et al 2019). SAMe is the methyl donor for the conversion of phosphatidylethanolamine to phosphatidylcholine and these lipids account for about 14% and 11%, respectively, of CNS myelin and inefficient conversion may impair myelination or cause demyelination (Dror and Allen 2008). The reaction involves the transfer of a methyl group from 5-MTHF to homocysteine, therefore another role regarding folate’s involvement in myelination as well (Scott 1999).
Methylcobalamin given at 60mg orally every day for six months to six patients with progressive MS did not improve motor disability but improved abnormalities in both the visual and brainstem auditory evoked potentials (Kira et al 1994). MS patients given 1mg of Methylcobalamin weekly for six months did result in improvements on a neurological disability scale (Loder et al 2002). Given this information, intake of at least 1mg of methyl-B12 per week is reasonable for a patient with MS.
A more sensitive proposed method of screening for Cobalamin deficiency is the measurement of methylmalonic acid and homocysteine blood levels, which are increased early in vitamin B12 deficiency (Miller et al 2005). Data has suggested that elevated homocysteine, and depressed vitamin B12 and folate serum levels may be associated with MS but historically findings are not always consistent. However, a 2020 meta-analysis found elevated homocysteine in RRMS only, with no differences in serum B12 or folate from looking at 21 studies with 1738 MS patients and 1424 controls (Li et al 2020). However, lower median cerebrospinal fluid vitamin B12 concentrations were found in groups of patients with MS compared to serum levels, yet this was not found with regards to folate concentrations (Nijst et al 1990). MS patients with hyperhomocysteinemia have shown higher disease progression evaluated by the Multiple Sclerosis Severity Score and EDSS. Hyperhomocysteinemia may reflect issues with methylation and hypomethylation of myelin basic protein (a major component of CNS myelin) can destabilize the structure of myelin, and may hinder remyelination or myelin repair (Dardiotis et al 2017). Inborn errors involving the genes of the methyl transfer pathway are known to cause inadequate myelination and serious disability from childhood (Van Rensburg et al 2006).
Pharmacologic dosing of biotin (B7) has recently gained notoriety as a treatment for myelination in MS and has been studied extensively. Biotin serves as a coenzyme for biotin dependant carboxylases that facilitate the transfer of a carboxyl (COOH) group to substrates (Zempleni et al 2009). Acetyl-CoA carboxylase produces malonyl-CoA from acetyl-CoA and citrate. The synthesis of malonyl-CoA represents the rate-limiting step of long-chain fatty acid synthesis in oligodendrocytes for use in myelin production, as malonyl-CoA is two-carbon building block for fatty acid synthesis. Most studies regarding biotin used 300mg daily, which is 10,000-fold higher than the Adequate Intake (AI) recommended. Therefore, serious exploration regarding the efficacy of its data is warranted (Sedel et al 2016).
A pilot trial administered 100mg to 600mg/day of biotin (with a median of 300mg/day divided in three doses) in 23 primary and secondary progressive MS patients for two to 36 months (mean duration of 9.2 months). Five patients with chronic visual loss had improvement of visual acuity after a delay of two to three months. Sixteen of eighteen patients with prominent involvement of the spinal cord (with tetra and paraparesis) displayed clinical improvement after a two to eight-month delay. Two patients did not respond at all. The EDSS score significantly improved in 4/23 patients (22%) and Timed 25 Foot Walk (TW25) improved in 5/7 cases with paraparesis. Four patients experienced at least one MS relapse but it was suggested the frequency was similar to that observed before treatment in these patients (Sedel et al 2015).
A follow‐up study (MS-SPI trial) used 300mg/day (three 100mg doses per day) “MD1003” versus placebo in 154 patients with progressive MS (103 received biotin and 51 received placebo) for 12 months. A total of 13 (12.6%) biotin treated patients achieved reduced disability at month nine, confirmed at month 12 (mean EDSS decreased slightly from baseline) versus none of the placebo-treated patients (EDSS increased at the expected rate). MRI found new lesions in 23.4% of biotin-treated patients and 13.0% placebo-treated patients possibly raising the concern of increased disease activity (Tourbah et al 2016).
Another study by the same investigator, used the same dosing strategy in a six-month, randomized, double-blind, placebo-controlled study with a six-month open-label extension phase, in adult patients with MS-related chronic visual loss. Ninety-three patients received biotin (45 of which had RRMS, and 20 with Progressive MS) and 28 received placebo. At six months, there was an improvement in visual acuity in the biotin group relative to placebo but difference between arms was not significant. The incidence of MS relapse was higher in the biotin group (13.8%) than in the placebo group (3.6%) during the double-blind phase of the study, raising the concern again that high dose biotin might actually increase disease activity (Tourbah et al 2018).
An observational study was published describing 178 progressive multiple sclerosis patients who started high-dose biotin at two hospitals over an approximate 27-month period. At 12 months, 3.8% of the patients had an improved EDSS score. However, 47.4% of the patients described stability, 27.6% felt an improvement and 25% described a worsening (Couloume et al 2020).
In another observational study, 43 patients with progressive multiple sclerosis were prescribed a single daily dose of 300mg of biotin for one year with only 56% completing that period. Twenty-six patients had secondary progressive MS, seven patients had primary progressive MS, ten patients had RRMS. None of the patients’ EDSS scores improved and one-third of patients worsened. These authors were concerned that biotin-induced increases in energy metabolism in diseased axons, along with lack of access to other necessary energy metabolites, may have resulted with axonal decompensation, and worsening of function (Birnbaum and Stulc 2017).
Lastly, a double-blind, placebo-controlled trial (SPI2) with 642 patients who had no relapses in the two years before enrolment where 64% had secondary progressive MS and 35% had primary progressive MS was conducted. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25, and biotin was administered at 100mg TID. Thirty-nine (12%) of 326 patients in the biotin group compared with 29 (9%) of 316 in the placebo group improved at month 12. Twenty-nine (9%) participants in the biotin group and 31 (10%) in the placebo group experienced relapses, and no differences in MRI outcomes were observed (Cree et al 2020). The relapse and MRI outcomes may reduce concern raised by Tourbah and colleagues (2016, 2018) regarding higher disease activity with high-dose biotin.
It is unclear why the pilot trial of Sedel and colleagues (2015) results were greatly different from Cree and colleagues (2020) as both had similar age and initial EDSS. Mechanistically, it makes sense to include sufficient biotin nutritionally speaking as a factor for myelination but it appears that pharmacologic dosing of biotin does not consistently provide benefit. It is plausible that despite enhancing one rate-limiting enzyme involved in myelination that patients may lack other necessary cofactors for this process. One group estimated that a biotin intake of 1mg daily would come close to maximizing the activity of holocarboxylase synthetase in the central nervous system which is needed to catalyze the formation of biotin-dependent enzymes for myelin synthesis (McCarty and DiNicolantonio 2017). It is worth mentioning biotin ingestion frequently causes laboratory errors for numerous biotinylated immunoassay-based laboratory tests such as free thyroxine, free triiodothyronine, thyroglobulin, dehydroepiandrosterone sulfate (DHEA-S), estradiol, testosterone, ferritin, progesterone, vitamin B12, prostate-specific antigen, parathyroid hormone, luteinizing hormone, and follicle-stimulating hormone. With high dose biotin reported to have a half life of up to 18.8 hours discontinuation for a few days prior to lab work is suggested (Li et al 2020).
Vitamin A is a generic term for a number of related retinoid compounds such as retinol (an alcohol) and retinal (an aldehyde) also known as “preformed vitamin A”. Retinal can be converted by the body to retinoic acid (RA), the form of vitamin A known to affect gene transcription typically activating retinoic acid receptors α, β and γ (Bar-El Dadon and Reifen 2017, Huang et al 2018). Preformed Vitamin A is highly unstable. To enhance stability, esterification with palmitic and acetic acid have yielded retinyl palmitate and retinyl acetate, respectively (Souganidis et al 2013). RA exists in two significant derivatives: 9-cis-RA and all-trans-RA (Huang et al 2018). Oligodendrocyte lineage cells appear to express retinoic acid receptor RXR-γ in tissues undergoing remyelination. Administration of 9-cis-RA to demyelinated cell cultures and to aged rats after demyelination caused an increase in remyelinated axons suggesting that the RXR-γ is a positive regulator of OPC differentiation and remyelination (Huang et al 2011). The glycosphingolipids galactosylceramide (cerebroside) i s the main sulfate acceptor in brain tissue to create sulfatide (the sulfated form) which are the most common lipids in myelin. Dietary Vitamin A deficiency in the period of myelination heavily depressed the formation of sulfate and sulfatide in vitro compared to the activities of normal developing rats with an identical age (Clausen 1969). Clinically, 35 MS patients were divided into two groups where one group was given 25,000IU/day vitamin A (as retinyl palmitate); in the vitamin A group, the peripheral blood mononuclear cells showed reduced proliferation when stimulated with myelin oligodendrocyte glycoprotein (Jafarirad et al 2012). In another study, 101 RRMS patients where the treatment group was administered 25,000IU/day retinyl palmitate for six months followed by 10,000IU/day for another six months showed significant improvements for fatigue and depression possibly through anti-inflammatory mechanisms, and none of the patients were excluded from the study because of adverse effects (Bitarafan et al 2016). All-trans-RA and 9-cis-RA appear to modulate the imbalance of Th17 and Treg cells (Abdolahi et al 2015). Furthermore, treatment of T cells with RA attenuated their ability to induce disease in experimental autoimmune encephalomyelitis (EAE), a murine model for MS (Raverdeau et al 2016). Therefore, inclusion of vitamin A may not only help in part to facilitate myelination but may also have beneficial immunomodulatory effects. Similar dosing to these studies is suggested because of apparent benefit and safety demonstrated.
Vitamin K exists in two main natural forms: K1 (or phylloquinone) and K2 (menaquinone including several different vitamers). Menaquinones are classified according to the length of their unsaturated side chains from MK-4 (shortest) to MK-15. MK-4 is produced by systemic conversion of K1, and MK-7 through MK-10 are synthesized by bacteria in humans (Fusaro et al 2017). Phylloquinone is mainly found in green vegetables. Liver is a rich source of menaquinones, which are also in meats, cheese and eggs (Cozzolino et al 2019).
MK-4 is the predominant form of vitamin K measured in the human brain and concentrations are higher in myelinated areas. As mentioned, pyridoxal 5’-phosphate is a cofactor for serine palmitoyltransferase and for sphingomyelin synthesis. These processes appear to depend on Vitamin K which influences the activity of galactosyl-ceramide sulfate transferase (also called cerebroside sulfotransferase), the enzyme that catalyzes the conversion of cerebrosides to sulfatides (Denisova and Booth 2005).
Vitamin K2 levels were assessed in 45 MS patients (predominantly females with RRMS) and 29 healthy controls (also mostly women). The assay measured all varieties of K2. The MS patients had more than three-fold lower K2 blood levels than controls (235 ± 100ng/ml vs. 812 ± 154ng/ml, respectively) and female patients had significantly lower K2 levels than males. Lower levels correlated with increased relapses per year. One proposed explanation was increased consumption of K2 by tissues for remyelination (Lasemi et al 2018). Regarding MS, using the cuprizone demyelination model, mice were allowed to remyelinate in the absence or presence of K1, whose presence enhanced the production of total brain sulfatides (Popescu et al 2018).
Adequate intake for adult females is 90mcg and 120mcg daily for adult males and despite its fat solubility, no tolerable upper intake level has been set (Turck et al 2017). Pharmacologic doses of 45mg/day of MK-4 to osteoporotic patients for 24 months has been shown to be safe (Shiraki et al 2000). Pharmacologic doses of 5mg of K1 for up to four years have also shown to be safe in post menopausal women (Cheung et al 2008). Vitamin K1 supplementation at 10mg/day for eight weeks was well tolerated in women with Rheumatoid Arthritis, perhaps further reflecting safety in autoimmunity (Shishavan et al 2016). Because MK-4 is the dominant form in the brain, contextually in MS it may be advantageous to ensure intake of MK-4 through animal sources and supplementation of at least 90-120mcg is recommended considering prevalence of deficiency if dietary intake is in doubt. Be advised that Vitamin K interacts with some medications such as anticoagulants possibly beyond intake of 150mcg daily (Violi et al 2016).
Iron also appears indispensable for myelin synthesis. Iron deficiency in early life is associated with hypomyelination. In both pre and post natal development, iron is an essential factor in myelination and oligodendrocyte biology, as disruption of iron availability in animal models results in a decrease in myelin proteins and lipids (Ortiz et al 2004). In the brain, cellular accumulation of iron is highest in oligodendrocytes which further implies a critical role of iron in their function (Hauser et al 2020). Many of the enzymes involved in the physiological pathways that produce myelin utilize iron as part of their catalytic center (such as lipid saturase and desaturase) and the demand for iron is also high because myelinogenesis is highly energy-intensive (Grishchuk et al 2015). Serum iron and ferritin concentrations were significantly lower in the MS subjects compared to matched controls with median ferritin 32.00 in MS patients versus 54.22 in controls in 27 females and 3 males (Van Rensburg et al 2006). Low ferritin may have implications for MS fatigue.
Data suggests that ferritin is the main iron transport mechanism to oligodendrocytes, as one molecule of transferrin or lactoferrin has the ability to carry two molecules of iron whereas, ferritin can bind up to 4,000 molecules of iron in its core (Hulet et al 1999). Ultimately, when one is attempting to encourage myelinogenesis, ensuring iron sufficiency is of importance, possibly by ensuring sufficient ferritin saturation. However, because age-related iron accumulation in the human brain is associated with neurodegeneration of progressive MS, it is reasonable to not do this in excess (Mahad et al 2015).
Manganese, copper and zinc appear to have roles in myelination but their exact roles are not well elucidated (Bourre et al 1987). In the Cuprizone MS model, cuprizone is a copper chelator, which when ingested by mice, causes copper deficiency and oligodendrocyte degeneration and demyelination (Popescu et al 2018). Clinically, until more is known, the inclusion of a general multivitamin with appreciable mineral content is warranted.
Citicoline is the generic name of cytidine-5′-diphosphocholine or CDP-choline, but this, as with other phosphorylated substrates, are considered unable to penetrate cell membranes (Grieb 2014). Citicoline is degraded to cytidine and choline during hydrolysis and dephosphorylation in the blood which easily pass the blood-brain barrier (Jasielski et al 2020). Endogenously, formation of citicoline from choline is the rate-limiting step in the synthesis of phosphatidylcholine, as previously discussed as one of the most abundant lipids in myelin (Weiss 1995). In the CNS, acetylcholine synthesis is favored when the available amount of choline is limited, therefore choline is preferentially used to produce acetylcholine, which limits choline available for phosphatidylcholine production (Conant and Chauss 2004). Cytidine undergoes cytoplasmic conversion to cytidine triphosphate (CTP). Choline is phosphorylated by choline kinase into phosphorylcholine which combines with CTP to form citicoline. Citicoline then combines with diacylglycerol forming phosphatidylcholine (via choline phosphotransferase) for repair of neuronal membranes (the CDP-Choline Pathway or the Kennedy Pathway) (Clark et al 2008). Endogenously, choline is synthesised from ethanolamine by three successive methylations once again implicating MTHF and methylcobalamin (Van Rensburg et al 2006). Citicoline has other relevant neuroprotective effects which include reducing glutamate excitotoxicity, and supporting axon regeneration (Gandolfi et al 2020). Citicoline serves as an intermediate in the synthesis of sphingomyelin, another neuronal membrane phospholipid component (Adibhatla and Hatcher 2002).
Citicoline was studied in EAE (Experimental Autoimmune Encephalomyelitis) and in the cuprizone model of demyelination to test the hypothesis that Citicoline directly increases remyelination. In the EAE model, Citicoline ameliorated the disease course and exerted beneficial effects on myelin, oligodendrocytes and axons. After cuprizone-induced demyelination, it enhanced myelin regeneration and reversed motor deficits. An increase in the numbers of proliferating OPCs and oligodendrocytes were found. No differences were found in any immunologic parameters (T Cells, cytokines, microglia) between treatment and control groups, indicating the observed effects were not due to immunomodulation (Skripuletz et al 2015).
Relevant mechanisms of citicoline in MS include Sirtuin activation as treatment with citicoline increased SIRT1 protein levels in experimental models (Hurtado et al 2013). SIRT1 is a histone deacetylase that is involved in longevity and plays a role in neuronal health during aging (Herskovits and Guarente 2014). The choline moiety from citicoline can be metabolized to betaine, which serves as a source of methyl groups, and through metabolism to SAMe serves to turnover homocysteine to cysteine and ultimately glutathione which has neuroprotective qualities (Adibhatla and Hatcher 2002). Choline in citicoline is less prone to conversion to potentially atherogenic product trimethylamine N-oxide (TMAO); conversion to TMAO is mediated at the level of the gut whereas citicholine degradation happens in the blood (Synoradzki and Grieb 2019). Combined citicoline and DHA synergistically and significantly improved learning and memory ability in a brain ischemia model compared to either alone, indicating the concept of enhanced synergistic effects in neuronal injury (Nakazaki et al 2019).
Oral Citicoline dosed 500mg twice a day was effective and safe in the treatment of mild vascular cognitive impairment over a nine-month period (Cotroneo et al 2013). Doses of 2000mg daily have also been shown to be well tolerated in humans with antidepressant and cognitive enhancing effects over a 12-week period (Brown and Gabrielson 2012, Gavrilova et al 2011). Therefore, 1000-2000mg daily for at least 12 weeks is a reasonable dose strategy to consider since both have been shown to have an effect on brain related parameters in humans.
Lithium has emerged as a neuroprotective agent through multiple mechanisms including inducing BDNF, inhibiting glycogen synthase kinase-3beta (GSK3β) activity and indirectly inhibiting N-methyl-D-aspartate (NMDA)-receptor glutamate-mediated calcium influx (Rowe and Chuang 2004). Inhibition of GSK3β stimulates OPC proliferation and myelination via the canonical Wnt signaling pathway by stimulating nuclear translocation of β-catenin (Azim and Butt 2011).
In one study, 44 RRMS patients were compared to 43 matched healthy subjects revealing a statistically significant difference with regards to serum lithium concentrations. Lithium was found to be remarkably lower in RRMS (0.57 ± 0.2µg/l) compared to controls (2.29 ± 0.7µg/l) (Karimi et al 2017).
In EAE, lithium carbonate administration has been studied in a dose strategy commonly used to achieve serum levels equivalent to those attained therapeutically in human patients. Pre-treatment with lithium markedly suppressed the clinical symptoms of EAE with reduced demyelination, microglial activation, and leukocyte infiltration in the spinal cord. Furthermore, lithium administered after disease onset reduced disease severity and facilitated partial recovery (De Sarno et al 2008). Converting the dose used in the trial, approximately 486mg would be used for a 60kg adult (Reagan-Shaw et al 2008).
Twenty-three patients with primary or secondary progressive MS were recruited into a two-year crossover trial in which subjects were randomly assigned to take a target of 300mg/day lithium carbonate, or 150mg/day if the larger dose was not tolerated in year one or two. Disability did not significantly change as measured by EDSS and MS Functional Composite. However, mood and mental parameters did improve. A possible stabilizing effect of lithium on brain volume was seen, but the study was underpowered to definitively detect change in brain volume as a therapeutic outcome (Rinker et al 2020).
Dosing for mood stabilization is frequently from 600 to 1200mg/day with necessary monitoring of renal and thyroid parameters (Malhi et al 2017). In a retrospective review of lithium usage in veterans with MS (to treat refractory mental health disorders), 101 veterans with MS who took lithium for more than six months were assessed. Annualized relapse rates were higher on Lithium but an increase in EDSS scores were greater in the off-lithium period than the on-lithium period. However, a consistent effect of lithium on MS disease activity was not apparent and its unclear if these subjects experienced a true acceleration of their disease or if their disease was independent of lithium treatment (Rinker et al 2013). Ultimately, it appears that therapeutic lithium dosing is not in and of itself highly beneficial with regards to improving disability.
Lithium orotate (LO) is non-prescription lithium source typically in doses of 5-20mg elemental lithium compared to 120-240mg elemental lithium in prescription lithium carbonate. LO dosing is thought to mimic the levels of lithium gained from living in areas where there are relatively high concentrations of lithium in the food chain and water supply. Orotate is said to act as a delivery system to transport the lithium ion efficiently through the cell membrane to its various sites of action within the cell (Devadason 2018). Ultra low dose lithium (400mcg daily) can improve mood parameters indicating that despite the low dose, it may affect brain parameters. 100mcg daily of lithium has been suggested as the intake for American adults (Schrauzer and de Vroey 1994). Although doses used in Rinker and colleagues (2020) did not appear to significantly affect EDSS, and higher doses in Rinker and colleagues (2013) were not clearly effective, it may make sense to rectify the lower levels observed in Karimi and colleagues (2017) in the scenario that there is increased demand for lithium as part of the pathogenesis, and LO may fit the role of rectifying those deficiencies.
Non-Nutritional Approaches
Thymosin beta4 (Tβ4) is a 43-amino acid peptide isolated originally from a thymic extract (Goldstein et al 2005). Tβ4 is a potent regulator of actin assembly in living cells (Sanders et al 1992). Outside of the CNS, Tβ4 exerts anti-inflammatory and anti-fibrotic effects, has potential in hepatic disease and renal disease, promotes cell migration and angiogenesis and has potential in corneal and cardiac disease (Jiang et al 2017, Lv et al 2020, Sosne et al 2007, Vasilopoulou et al 2015).
In the CNS, Tβ4 can enhance angiogenesis, neurogenesis, neurite and axonal outgrowth, but is thought to principally effect oligodendrogenesis. Tβ4 is thought to target multiple molecular pathways that drive oligodendrogenesis possibly by altering cellular expression of microRNAs (Chopp and Zhang 2015). MicroRNAs are small noncoding RNAs that adjust gene expression in the transcription stage, and in particular, Tβ4 stimulates the expression of miR‐146a which affects NF‐κB (Nuclear factor kappa B, a proinflammatory signaling pathway) and may be anti‐inflammatory controller in the CNS particularly regulating microglia (Shomali et al 2020).
Tβ4 is expressed in a wide variety of organs including throughout the CNS. Tβ4 is predominantly expressed in neurons as well as in microglia and neural progenitor cells with a number of repair functions related to cell proliferation, angiogenesis, and axonal remodeling (Pardon 2018). Tβ4 improves neurological functional outcome in a rat model of embolic stroke and traumatic brain injury (Morris et al 2012). Mice subjected to EAE were treated with saline or intraperitoneal Tβ4 and those with Tβ4 showed enhanced functional recovery and significantly increased OPCs and mature oligodendrocytes. Since the mature oligodendrocytes are post-mitotic and are unable to proliferate, it implies that the additional mature oligodendrocytes were from proliferating OPC differentiation (Zhang et al 2009). In a follow up study, EAE and the Cuprizone diet model were used to assess the effects of intraperitoneal Tβ4. Significantly increased OPC proliferation, mature oligodendrocytes, reduced axonal damage, enhanced remyelination and correlated functional recovery were seen in the Tβ4 treated EAE mice. Tβ4 treatment significantly increased OPC differentiation and remyelination in the Cuprizone model. Tβ4 effects on generation and differentiation of OPCs is thought to be mediated through epidermal growth factor receptor (EGFR) signaling in this study (Zhang et al 2016). Tβ4 may mediate these effects without crossing the blood-brain barrier (Osei et al 2018).
Tβ4 has been studied in humans. Topically administered Tβ4 was shown to accelerate wound healing in patients with venous stasis ulcers (Guarnera et al 2010). Endothelial progenitor cells (EPC) pre-treated with Tβ4, and then transplanted in patients with acute ST segment elevation myocardial infarction had an increased six-min walking distance as well as enhanced cardiac function compared to non treated EPCs (Zhu et al 2016). Topically administered Tβ4 reduced dry eye sign and symptom assessments in those with severe dry eye disease (Sosne et al 2015).
With regards to parenteral human data, for potential use in cardiac ischemia, four cohorts, with ten healthy subjects each, were given ascending doses of either 42, 140, 420, or 1260mg intravenous Tβ4 or placebo for 14 days. Individuals at increased risk for malignancy were excluded from this trial because of the possibility of Tβ4 influencing the metastatic potential of certain malignancies through its ability to promote angiogenesis and stimulate cell migration. Adverse events were infrequent and mild or moderate in intensity, and there were no dose limiting toxicities or serious adverse events (Ruff et al 2010). Dosing 750mcg delivered subcutaneously daily for 30 days, then delivered every other day thereafter has been suggested although this has not been formally evaluated (Martinez 2019).
Quetiapine (Seroquel) is a second-generation antipsychotic that is used primarily for bipolar disorder and schizophrenia (El-Saifi et al 2016). With regards to myelination, (platelet-derived growth factor) PDGF-induced cell cycle activation seems to keep OPCs in a proliferative state and hinders OPC differentiation. Quetiapine inhibits PDGF-induced cell cycle activation and promotes oligodendrocyte differentiation (Mi et al 2018). Quetiapine has been shown to enhance the expression of several neurotrophic factors in vitro and in vivo, such as BDNF (Zhang et al 2012). In terms of neurodegeneration, Quetiapine treatment appears to increase the activities of antioxidant enzymes, including superoxide dismutase and glutathione peroxidase (Xu et al 2018).
Quetiapine was able to dramatically attenuate the severity of EAE symptoms by decreasing T cell infiltration into the spinal cord and suppressing local glial activation (microglia and astrocytes), and therefore diminishes the loss of mature oligodendrocytes and myelin breakdown. Furthermore, Quetiapine appeared to promote oligodendrocyte precursor differentiation because an increased number of mature oligodendrocytes were found after treatment (Mei et al 2012).
Insomnia affects approximately 50% of patients with MS (Alhazzani et al 2018). Quetiapine’s antagonism of histamine H1 and serotonin type 2A receptors has a sedative effect and, as such, is widely used off-label as a treatment for insomnia. Quetiapine has been shown to improve sleep latency, total sleep time, and sleep efficiency compared with placebo at dosages of 25–75mg nightly and therefore can be considered a relevant agent for insomnia in MS patients (Anderson and Vande Griend 2014). Quetiapine has good tolerability at doses of 150 to 750mg/d for antipsychotic effects. However, hangover, dizziness, dry mouth, increased hepatic transaminase levels and abdominal pain are reported side effects (Cutler et al 2002). The effective dosage range is usually 300-450 mg/day (Green 1999). It has efficacy in major depressive disorder possibly through dopaminergic action in doses between 150-300mg daily (Ignácio et al 2018). Depressive disorders occur in up to 50% of MS patients, with prevalence estimated to be up to three times higher than those of the general population and as such Quetiapine may be indicated because of the high prevalence of comorbid depression (Patten et al 2017). Monitoring metabolic parameters such as weight, blood pressure, glucose and lipids as well as thyroid function is recommended with long term (six months) administration, especially if dosed at greater than 100mg per day (Carr et al 2016). Overall, the effects of Quetipine on sleep, mood and possibly myelination and inflammation, in addition to it being readily available and low cost, make it an important agent to consider in MS. One group translated the dose commonly used in animals (10mg/kg) to roughly equal of oral treatment in humans (Zhornitsky et al 2013).
Iodine as iodide is taken up by the thyroid gland and through the iodization of tyrosine, T4 (thyroxine) and subsequently T3 (triiodothyronine) is produced (Zbigniew 2017). Iodine deficiency therefore appears to affect myelination indirectly through its intimate role in thyroid hormone production (Wei et al 2015, Zimmerman 2011). For instance, no myelination was detected in the cerebral cortex of fetuses aborted at month eight of gestation in an iodine-deficient area of China and gestational iodine deficiency in sheep and rodents reduces myelination (Prado and Dewey 2014). In the cuprizone mouse model, T3 thyroid hormone administration increased adult oligodendrocyte numbers and ameliorated aberrant astrogliosis (Zendedel et al 2016). During development, thyroid hormones also promote myelination by enhancing oligodendrocyte differentiation (Hartley et al 2019). The combination of T3 and quetiapine has been found to have an additive effect on OPC differentiation and consequent myelin production (Franco 2008). A phase 1 study looked at the maximum tolerated dose of T3 therapy over one week in 15 patients with MS in preparation for a phase II trial (Wooliscroft et al 2020). It is reasonable to consider optimizing Free T3 levels in an MS patient given that fatigue is one of the most common symptoms in MS and that it may impact myelination, possibly even more so in conjunction with quetiapine which can be thyrosuppressive (Manjaly et al 2019). Targeting T3 levels in the mid or upper normal range may denote an optimal replacement strategy which is frequently employed in naturopathic and functional medicine (Clarke and Kabadi 2004). Furthermore, iodine deficiency is one of the most common micronutrient deficiencies, yet is frequently overlooked, and iodine status can and should be assessed by determining urinary iodine concentration (Redman et al 2016).
Sleep disorders have a higher prevalence in MS patients and can be the consequence of an injury of specific CNS areas (Foschi et al 2019). It is somewhat commonsensical that sleep is involved in repair and the same applies to neurological repair and remyelination. Not surprisingly, sleep plays a role in some oligodendrocyte processes, including myelination (Buratti et al 2019). In fact, differential expression of genes occurs in oligodendrocytes during sleep; oligodendrocyte genes involved in phospholipid synthesis and myelination or promoting OPC proliferation are transcribed preferentially during sleep. Therefore, it may be advantageous to dose discussed potential pro-myelinating substances before bed (Bellesi et al 2013). Adequate restorative sleep will likely serve to improve neurological repair, so screening for and rectifying sleep disorders is recommended.
Exercise, in terms of hormesis, could impose a mild stress on neurons resulting in activation of transcription factors that induce stress-resistant proteins like BDNF. Regular physical activity may have value in MS partly through other exercise-mediated neurotrophic factors like Insulin-Like Growth Factor (IGF-1) and Nerve Growth Factor (NGF) (White and Castellano 2008). Subcutaneously administered IGF-I upregulated synthesis of myelin proteins and myelin regeneration, and caused a dramatic improvement in EAE (Yao et al 1996). Intracerebroventricularly placed NGF prior to the induction of EAE has significantly reduced disease severity (Parvaneh Tafreshi 2006). Studies on motor rehabilitation support the notion that brain plasticity is preserved even in chronically disabled patients with MS, which suggests that exercise and rehabilitation are important elements to overcoming part of the physical disability (Prosperini et al 2015). In particular, task-oriented training best yields rehabilitation-induced plasticity (Prosperini and Di Filippo 2019). Electrically active axons are preferentially myelinated and this gives insight into the known positive influence of physical activity on wellbeing in multiple sclerosis (Lubetzki et al 2020). Exercise and rehabilitation may also induce compensatory adaptive changes irrespective of potential impact on myelination (Flachenecker 2015).
Hyperbaric Oxygen Therapy (HBOT) has several mechanisms relevant in mediating neurological injury including: increasing tissue oxygenation, reducing inflammation, decreasing apoptosis and promoting neurogenesis and angiogenesis (Hu et al 2016). There is evidence that repetitive HBOT improves outcomes in traumatic brain-injured patients, and animal models suggest that enhanced remyelination in the injured areas is part of the mechanism through which the HBOT works (Kraitsy et al 2014). Stem cell release is frequently reported with HBOT, for instance, neonatal hypoxic-ischemic rats treated with HBOT had proliferation of endogenous neural stem cells and an increase in newly generated neurons (Yang et al 2008). However, strong in vivo promyelinating effects have not been demonstrated in models of MS. Some promising human data has emerged. In a study, 40 patients with advanced chronic multiple sclerosis were randomly divided into two groups and treated at pressures of 2.0ATA (atmosphere absolute) for 90 minutes over twenty treatments with either pure oxygen or 10 percent oxygen. Objective improvement (mobility, fatigue, balance and bladder function) occurred in 12 of 17 patients treated with hyperbaric oxygen and in 1 of 20 patients treated with placebo (Fischer et al 1983). However, numerous other trials have failed to find a substantial effect evaluating HBOT over a course of twenty treatments (Confavreux et al 1986, Harpur et al 1986, Wiles et al 1986, Wood et al 1985). It has been suggested that 20 consecutive treatments may have been insufficient for the majority of those treated or that the treatment period was insufficient. For instance, one longer term study looked at 44 MS patients (22 in the 100% oxygen group and 22 in the compressed normal air group) receiving 2.5ATA for 90 minutes initially for one month, then multiple “booster” treatments weekly over a one-year period. In the Hyperbaric group, 14/22 reported benefits, four reported no change and four declined. Whereas only two in the Hyperbaric air group reported benefit. Interestingly, it took six months before major changes were noted (Oriani et al 1990). At this point it appears that although not apparently detrimental, it is unclear whether only a subset of MS patients responds to HBOT or whether longer term treatment protocols are needed.
Synergistic Approaches
One group investigated the impact of a nutrient blend (containing DHA, arachidonic acid, vitamin B12, vitamin B9, iron and sphingomyelin) or each of these nutrients individually, on OPCs as well as their myelinating properties. In particular, the nutrient blend increased the number of OPCs and promoted their differentiation into oligodendrocytes. Each nutrient dose was selected based on a pilot study using, 1X, 10X or 100X of the known human adult cerebrospinal fluid concentration, using the highest dose with the least toxic effect. The beneficial effects seemed to be dose-dependent as lower doses of the blend failed, implying that human dosing might need to be supraphysiological or pharmacologic.
Treatments with iron, B12, folate and sphingomyelin all resulted in a positive effect on differentiation (albeit of a smaller magnitude) in vitro, suggesting that differentiation OPCs benefit, to some extent, from the net synergistic effect and interaction between nutrients compared to only using individual nutrients (Hauser et al 2020). It is note worthy that arachidonic acid, on its own, was inhibitory to every single myelination parameter perhaps suggesting excess omega-6 fatty acids may not be beneficial for myelination.
A study using a modified Paleolithic dietary intervention (MPDI), where eight subjects (one male) and nine controls (one male) completed the dietary intervention over a three-month period. The diet is described as nine cups of vegetables and some fruits, meat protein including organ meat, and complete abstinence from products containing gluten, dairy, potatoes, and legumes. Significant improvements were seen in Fatigue Severity Scale score, the Multiple Sclerosis Quality of Life-54 (mental and physical quality of life), and time to complete (dominant hand) 9-Hole Peg Test from baseline compared to controls. Subjects in both groups demonstrated improved gait but the MPDI group subjects tended to improve more than controls (Irish et al 2017).
The diet uses both plant and animal sources of Vitamin K. The diet maximizes many nutrients but the highest nutrient using this approach is Vitamin K. Increased vitamin K serum levels (262% increase from baseline) were observed in the subjects, and intake was estimated 600% of the adult adequate intake, with 533µg vitamin K per 1000kcals (Irish et al 2017). Since Irish and colleagues (2017) showed improved measurable parameters, with Vitamin K as the most enhanced nutrient in the study, it may be sensible to maximize dietary Vitamin K sources in a clinical setting with patients in an attempt to mimic the positive effects shown.
MPDI style menu was assessed for nutritional adequacy and average % Recommended Dietary Allowance (RDA) was >300%. Vitamins B1, B2, B3, B6 and B12 were in excess of 500% RDA, likely due at least in part to the inclusion of nutritional yeast. On average, iron was 229.13%RDA, Zinc 224.88%RDA, Folate 262.88%RDA and Copper 378.50%RDA. Vitamin K levels were ≥888% Adequate Intake (AI) as the highest percentage of all nutrients, and Manganese was ≥ 269% AI and Choline was ≥91% AI, the lowest of the main identified myelinating nutrients (Chenard et al 2019). Therefore, although the results seen in Irish and colleagues (2017) seem to be weighted on Vitamin K, one cannot exclude the possibility that nutritional synergy contributed to the benefits seen.
In a 2020 trial, based on the premise of “reported neurologic synergistic effects of B1 (thiamine), B6 (pyridoxine), and B12 (cyanocobalamin)”, sixteen patients diagnosed with RRMS and visual disability following acute optic neuritis, were given 300mg of vitamin B1 (as thiamine), 450mg of vitamin B6 (as pyridoxine) and 1,500mcg of vitamin B12 (as cyanocobalamin) for 90 days. As an addition to disease-modifying therapies this improved visual function parameters including visual acuity (Mallone et al 2020). It is worth nothing that the dose of B6 is supratherapeutic, and is likely unsafe for long term use as some cases of sensory neuropathies have been reported at doses of less than 500mg, but over 200mg per day intake for months (Hemminger and Willis 2020). The dose of thiamine is likely safe for long term use as 300mg daily orally is used in the treatment of diabetic neuropathy (Rabbani et al 2009). Furthermore, B1 doses up to 1500mg daily have been used parenterally in Wernicke encephalopathy (Latt and Dore 2014). As discussed above, B12 doses up to 60mg have been used (Kira et al 1994). Trials like these imply synergy between the B vitamins, however, if a low number of individual nutrients are used, they may require supratherapeutic dosing for effect.
In a six-month pilot study looking at a nutrient regimen designed to promote myelin regeneration, the “Raphah Regimen”, which anecdotally showed symptom improvement of some MS subjects, was used. Iron supplements (15mg/day) were prescribed for those who presented with lower iron status. Essential amino acids, 500mg of Evening Primrose oil, 500mg of salmon oil, 300mg lecithin, and essentially a multivitamin and mineral were given. Of note, all B vitamins, zinc, copper and manganese were given. Methylation was optionally enhanced by additional weekly vitamin B12 injections, or a 1mg/day sublingual B12 supplement (presumably both methylcobalamin) or S-adenosyl methionine (SAMe) at 200mg/day (Van Rensburg et al 2006).
After six months, in 12 “compliant” RRMS patients, the mean total EDSS score improved significantly from 3.50 at baseline to 2.45 at endpoint with a large benefit in mood, whereas the EDSS in the “non-compliant” group had increased from 4.83 at baseline to 5.50. Both groups had significantly reduced homocysteine concentrations at six months, suggesting that methylation is necessary but not solely sufficient for myelin regeneration (Van Rensburg et al 2006).
The authors commented on the synergistic use of a number of relevant nutrients as follows: “if myelin production is compared to a production line in a factory, it would be reasonable to provide all the raw materials in adequate quantities on a continuous basis rather than provide only one constituent at a high concentration.” In this study, myelination was implied through functional improvement. This in essence demonstrates that nutritional synergy can be essential for functional improvement and that pharmacologic dosing is perhaps not always essential as large doses were not utilized in this study (Van Rensburg et al 2006).
Preliminary Areas
Taurine is one of the most abundant amino acids in the brain and throughout the body. Taurine serves a wide variety of functions in the central nervous system including neuroprotection by suppressing glutamate-induced toxicity via inhibition of calcium influx (Ripps and Shen 2012). Levels of taurine were found to be elevated 20-fold during the course of oligodendrocyte differentiation and maturation. Furthermore, when taurine was added at physiologically relevant concentrations, it dramatically enhanced in vitro OPC differentiation and maturation (Beyer et al 2018). Taurine directly increases the intracellular availability of the amino acid serine, which serves as a critical building block for phosphatidylserine glycosphingolipid synthesis in myelination (Rosko et al 2019). Taurine at 1500mg daily in conjunction with exercise has been shown to decrease inflammation, maintain blood-brain barrier integrity and enhance cognition in older adults (Chupel et al 2018, Chupel et al 2021).
Creatine is a nonessential amino acid that does not enter into protein composition (Balestrino and Adriano 2019). Creatine, through its intermediate phosphocreatine, provides a necessary cellular reserve of high-energy phosphates for ATP formation (Ryu et al 2005). Data that suggest creatine synthesis is required for the survival of newly generated oligodendrocytes during remyelination and that the administration of creatine into the CNS significantly improves oligodendrocyte viability during CNS remyelination, likely through enhanced energetics (Chamberlain et al 2017).
Pyrroloquinoline quinone (PQQ) is water soluble quinone distributed ubiquitously in nature and found in numerous dietary sources, including tea, green peppers, parsley, kiwi fruit, but is not endogenously produced by humans. PQQ is well known to have the ability to catalyze continuous redox cycling (Akagawa et al 2016). Nerve growth factor (NGF) was the first neurotrophin discovered for its stimulatory effect on differentiation, survival, and growth of neurons in peripheral and central nervous system (Colafrancesco and Villoslada 2011). NGF has been found to promote synthesis of myelin sheaths by myelin forming cells in CNS and PNS, as well as differentiation of oligodendrocytes (Razavi et al 2015). NGF promotes axonal regeneration, facilitates migration of OPCs to the sites of myelin damage and NGF induces the production of BDNF (Acosta et al 2013). PQQ stimulates NGF and was found to be a potent enhancer for the regeneration of peripheral nerves in a sciatic nerve model (Liu et al 2005). In a Parkinson’s model, PQQ suppressed the up-regulation of pro-inflammatory factors, such as IL-1β, IL-6 and TNF-α from microglia (Zhang et al 2020). Effects on human brains have been demonstrated as PQQ improved cognitive function in humans by improving regional cerebral blood flow and oxygen metabolism at a dose of 20mg (Nakano et al 2016).
Lion’s Mane (Hericium erinaceus) diterpenoids erinacine A, B, and C, from its mycelia, is another well known natural health product that stimulates NGF synthesis (Friedman 2015). Lion’s Mane promoted the regeneration of peripheral nerves in an animal model (Wong et al 2012), and it also triggered neurite outgrowth in brain and spinal cord cells in vitro (Samberkar et al 2015), though the immunostimulatory potential of its polysaccharides in the context of MS have not been elucidated. However, oral intake was shown to ameliorate experimental colitis by suppressing TNF-α, IL-1β, and IL-6 in colon tissues as well as adjusted the production of nitric oxide, malondialdehyde, and superoxide dismutase in serum to suppress oxidative stress, which suggests it might in fact be immunomodulatory (Qin et al 2016). Lion’s Mane may also reduce microglial activation (Kushairi et al 2019).
Short-chain fatty acids (SCFAs) are produced in the colon by bacterial fermentation of non‐digestible carbohydrates like soluble dietary fiber and have been shown to have immunomodulatory effects (Prasad and Bondy 2018). SCFAs can cross the blood-brain barrier (Wenzel et al 2020). Lack of SCFAs exist in MS patients, as gut dysbiosis and a depletion of fecal acetate, propionate, and butyrate was observed in MS patients compared to healthy controls (Zeng et al 2019). Short-chain fatty acids have been shown to ameliorate the disease course in EAE (Melbye et al 2019). Oral administration of antibiotics significantly enhanced cuprizone-induced demyelination whereas oral administration of butyrate significantly ameliorated demyelination independent of microglia. Furthermore, butyrate treatment facilitated the differentiation of immature oligodendrocytes, exemplifying the role of a healthy microbiome even in the context of demyelination (Chen et al 2019).
The mechanisms that regulate OPC differentiation are dysregulated in the aging brain, and preliminary evidence exists for caloric restriction as a restorative strategy. Fasting or treatment with metformin was found to restore the regenerative capacity of aged OPCs, improving remyelination in aged animals following focal demyelination (Neumann et al 2019). In mice, three, three-day cycles of a very low calorie and low protein fasting mimicking diet (FMD) (where on day one they consumed about 50% of their normal caloric intake and on days two to three they consumed about 10% of their normal caloric intake), showed reduced clinical severity in all mice and completely reversed symptoms in 20% of animals, as well as promoted OPC regeneration and remyelination in both EAE and cuprizone MS models. Mechanistically, up-regulation of AMP-activated protein kinase (AMPK) or down-regulation of mTOR Complex 1 (mTORC1), which contains the kinase mTOR, were proposed. AMPK and mTOR both sense nutrient availability and dictate cell fate (Choi et al 2016). Both mTOR and AMPK are considered master regulators of cell survival and metabolism (Garza-Lombó et al 2018). Furthermore, a modified FMD where 1/3 of control calories are consumed for three days, followed by ad libitum feeding for two cycles had significant decreases in EAE severity, immune cell infiltration in spinal cord, CNS demyelination, enhanced BDNF and improved remyelination markers such as expression of myelin basic protein and proteolipid protein (Bai et al 2021).
Summary of Clinical Recommendations
| Omega 3 fatty acids – minimum of 1.98g EPA and 1.32g DHA per day (possibly with a low-fat diet) Daily high potency B complex, possibly with MTHF, methyl and adenosylcobalamin Biotin – 1mg per day Daily multivitamin with zinc, copper, manganese Vitamin K2 – 90-120mcg MK-4 or higher per day Vitamin A – 25 000IU per day initially, then 10 000IU per day maintenance after six months Citicoline – 1000-2000mg per day Lithium Orotate – 5-20mg per day Addition of quetiapine and/or liothyronine/triiodothyronine, and/or thymosin beta4 Restorative sleep and daily exercise and/or physiotherapy Consideration of: taurine, creatine, PQQ, lion’s mane and intermittent fasting |
Concluding Thoughts
Finding remyelinating therapies to restore neuronal function and prevent axonal degeneration is still in its infancy yet is desperately needed. Although pharmaceutical strategies are in development, the use of principally nutritional techniques to hasten myelination is a promising area considering the pervasive roles and preliminary effects of nutrients identified herein. Because some patients are able to spontaneously remyelinate, identification of barriers to myelination for others is of utmost clinical interest. The possibility arises that some patients deficient in one or more nutrients may therefore impede the spontaneous remyelination process that can occur. Evidence exists for synergistic nutritional treatment as a promising area, in part because pharmacologic dosing of a single nutrient such as biotin has yielded suboptimal results. Finally, the use of existing agents known to enhance the well-known issue of OPC differentiation alongside synergistic nutritional strategies is worthwhile to explore for those currently suffering until better strategies are produced.
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