Part 1 is also online.

Introduction
Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS) that affects approximately 400,000 people in the US. MS is characterized by relapsing and remitting neurological dysfunction associated with acute episodes of inflammation. Last month featured Part 1 of this two-part update on multiple sclerosis. Part 1 explored common and uncommon etiologies, including genetics, smoking, latitude, vitamin D, viruses, hormones, solvents, heavy metals, stress, celiac disease, and air pollution. Treatments related to these etiologies include smoking cessation, stress management, vitamin D supplementation, dietary changes, hormone therapy, detoxification, and chelation. Many people with MS utilize conventional drug therapies and explore integrative modalities as well. Surveys suggest that up to 70% of people with MS have tried one or more alternative medicine, or integrative medicine, treatments to help control their MS symptoms.¹ In addition to treatments already discussed in Part 1, several other etiologies and integrative therapies for MS will be reviewed.

Resveratrol
Resveratrol is a polyphenolic compound produced by the skin of red grapes, peanuts, and other fruits. Most research on resveratrol has been conducted in cultured cells and animals. Recently its effect in mice with multiple sclerosis has been investigated. Optic neuritis is an inflammatory demyelinating disease of the optic nerve and often occurs as an acute episode of MS. A pharmaceutical-grade formulation of resveratrol was administered to mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The results showed that resveratrol prevented neuronal loss during optic neuritis. This is significant, as treatments that prevent neuronal damage during optic neuritis may have potential to prevent long-term visual loss and may have neuroprotective effects for other MS lesions.² A second study further investigated the mechanism of resveratrol's neuroprotective effect and found that in animal models of MS it can prevent neuronal loss without immunosuppression. In addition to preventing loss of neurons, at daily doses of 250mg/kg, resveratrol delayed the development of neurologic dysfunction in mice with EAE.³ The use of resveratrol in persons with multiple sclerosis sounds promising; however, studies need to be conducted on its use in humans.

Inosine
It has been shown that lower serum uric acid (UA) levels in MS patients are associated with relapse and that serum uric acid might serve as a possible marker of disease activity in MS.⁴ Raising uric acid levels can be beneficial in the treatment of MS and inosine supplementation is emerging as a method of achieving this goal. After oral administration of uric acid failed to increase low serum UA levels, evidently due to its degradation by gastrointestinal bacteria, researchers turned to its precursor inosine. In a small study, 3 of 11 patients with MS given inosine showed evidence of clinical improvement and there was no sign of new lesions on MRI in the remaining patients.⁵ Inosine is a purine nucleoside. After oral ingestion it produces uric acid, which has peroxynitrite scavenging activity. Peroxynitrite, a toxic product of the free radicals nitric oxide and superoxide, has been implicated in the pathogenesis of CNS inflammatory diseases, including multiple sclerosis.⁶ Inosine is often used by body builders and athletes for its supposed effects of energy and performance. More research is evolving in the use of inosine with persons with MS. In a double-blind randomized control trial of 16 patients with MS, oral administration of inosine raised uric acid levels which was correlated with decreased gadolinium-enhanced lesions and MS symptoms. Raising UA levels decreased serum nitrotyrosine while increasing the ratio of Th2 to Th1 cytokines in circulating cells. The only side effect was kidney stone formation in 4/16 subjects.⁷ These are small yet promising studies on the use of inosine for treating MS.

Green Tea
Green tea properties are being studied for their effects in several disease process and conditions. The main constituent of green tea is epigallocatechin-3-gallate (EGCG). In EAE, green tea reduced clinical severity when given at initiation or after the onset of EAE by both limiting brain inflammation and reducing neuronal damage.⁸ Green tea has both anti-inflammatory and neuroprotective effects. The human dosage equivalent to what was used in this study is contained in 3 liters of conventionally brewed green tea. A more recent study combined green tea with a common conventional medication for MS, glatiramer acetate (GA). In an animal model of MS the combination of green tea extract plus GA delayed disease onset, strongly reduced clinical severity, even after onset of symptoms, and reduced inflammatory infiltrates.⁹ EGCG in green tea has immunomodulatory and neuroprotective effects that may be beneficial in the management of MS.

Lipoic Acid
Lipoic acid (LA) is a potent antioxidant with several reported benefits and uses. In a randomized, double-blind, placebo-controlled study, 37 patients with multiple sclerosis took lipoic acid for 2 weeks. Patients were divided into 4 groups: placebo, LA 600 mg twice a day, LA 1200 mg once a day, and LA 1200 mg twice a day. The purpose of the study was to determine the effects of lipoic acid on matrix metalloproteinase-9 (MMP-9) and soluble intercellular adhesion molecule-1 (sICAMP-1). High levels of these proteins are associated with relapsing-remitting MS. The results showed that patients taking 1200 mg LA had substantially higher peak serum LA levels than those taking 600 mg and that oral LA can reduce serum MMP-9 and sICAM-1 levels. Although this is a small study, lipoic acid may be useful in treating MS.¹⁰ Other studies have shown that lipoic acid is effective in treating EAE, and optic neuritis associated with MS.¹¹

Omega- 6 Fatty Acids
Gamma-linolenic acid (GLA) is an omega-6 essential fatty acid that must be obtained from the diet. Research has shown a disturbance in omega-6 fatty acid metabolism in patients with MS and a role for omega-6 supplementation. In a randomized, double-blind, placebo-controlled trial of a high-dose and low-dose GLA-rich oil and a placebo control, the high-dose GLA significantly decreased the relapse rate and the progression of relapsing-remitting MS.¹² Another study looked at the effects of oral feeding of GLA from Borago officinalis to mice with MS and found protection from disease relapse.¹³ Although GLA appears to be a promising addition to disease management, several other studies on omega-6 supplementation in patients with MS have provided mixed results.

Omega-3 Fatty Acids
Omega-3 fatty acids are polyunsaturated fatty acids also commonly used in the management of patients with multiple sclerosis. Eicosapentanoic acid (EPA) and docosahexanoic acid (DHA) are two omega-3 fatty acids that are synthesized from linolenic acid in humans. Linolenic acid conversion to EPA and DHA in humans results in a very low amounts of EPA and DHA, which is why most EPA and DHA is supplemented through eating fish or taking fish oil. Several studies have shown that supplementing EPA and DHA in patients with MS results in a decrease in inflammatory cytokines and MMP-9. MMP-9 appears to be important for T-cell migration into the CNS in MS.^14,15 However, a recent randomized, double-blind, placebo-controlled clinical trial conducted from 2004 to 2008 looked at whether omega-3 fatty acids reduce magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis, both as monotherapy and in combination with interferon beta-1a treatment. The study concluded that no beneficial effects on disease activity occurred from omega-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a.¹⁶ While omega-3 fatty acid therapy has some benefits with MS, more research needs to be done.

Gamma-Aminobutyric Acid (GABA)
There is some evidence to consider the role of GABA in patients with MS. GABA is the main inhibitory neurotransmitter in the central nervous system. It is converted from glutamic acid by the action of glutamic acid decarboxylase (GAD). MS may be associated with low serum levels of GABA and its synthetic enzyme GAD. One study showed that the level of GABA and the GAD activity in the blood serum of MS patients was reduced as compared with the controls.¹⁷ This would make one wonder if manipulating GABA levels could be a possible treatment for MS. A 2010 study explored the use of GABAergic agents in a mouse model of MS (EAE). It found that increasing GABAergic activity improves paralysis and the number of relapses in EAE by decreasing inflammation. GABAergic agents act to diminish inflammatory responses to myelin proteins.¹⁸ The GABAergic agents used were vigabatrin and gabaculine, which increase GABA, topiramate, whose mechanism of action is unknown, and muscimol, a GABA structural analog. It appears by increasing GABA there was an improvement in MS in animal models due to GABA's role in decreasing inflammation. This possibly opens the door to study the effects of GABA supplementation in humans with MS.

It is interesting to note that inflammation inhibits GABA transmission in multiple sclerosis.¹⁹ Lower levels of the inhibitory neurotransmitter GABA can cause an increase in the excitatory neurotransmitter glutamate, which is known to be elevated in persons with MS.^20,21 The link between neurotransmitter changes and MS was noted years ago, showing that people with MS have high levels of glutamate, noradrenaline, glutamine, asparagine, and glycine.²² There are several labs that test neurotransmitter levels in the saliva and urine, and natural treatments to balance neurotransmitter levels are very effective.

Summary
Multiple sclerosis (MS) is a neurological disorder affecting hundreds of thousands of people in the US. MS involves an autoimmune response within the central nervous system with elements of inflammation, demyelination, and axonal injury. Part 1 of this column explored the link between the HLA DR2 gene, smoking, vitamin D, the varicella zoster and Epstein-Barr viruses, hormones, stress, celiac disease, heavy metals, solvents, and ambient air pollution. Part 2 of this review made it clear that the etiology of multiple sclerosis is multifactorial with further evidence linking MS to uric acid and neurotransmitter levels, oxidation, inflammation, and free radical damage. It also looked at additional nonpharmaceutical therapies for MS. New research has opened the door to explore integrative therapies such as botanicals, antioxidants, amino acids, vitamins, fatty acids, diet and lifestyle changes, detoxification, and hormone and chelation therapy. Although multiple sclerosis is a chronic disease with no definitive cause or cure, it is important to examine new risk factors, etiologies, and integrative treatments in an attempt to slow disease progression and manage symptoms so people with MS can have normal to near-normal function.

Notes
1.  Yadav V, Shinto L, Bourdette D. Complementary and alternative medicine for the treatment of multiple sclerosis. Expert Rev Clin Immunol. 2010; 6(3): 381–395.
2.  Shindler KS et al. Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroophthalmol. 2010;30(4):328–339.
3.  Fonseca-Kelly Z, et al. Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Front Neurol. 2012;3:84. Epub 2012 May 24.
4.  Toncev G. Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood-brain barrier dysfunction. Eur J Neurol 2002;9(3):221–226.
5.  Spitsin S et al. Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease. Mult Scler. 2001;7(5):313–319.
6.  Rentzos M et al. Serum uric acid and multiple sclerosis. Clin Neurol Neurosurg. 2006;108(6):527–531
7.  Markowitz CE et al. The treatment of multiple sclerosis with Inosine. J Altern Complement Med. 2009; 15(6): 619–625.
8.  Aktas O et al. Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol. 2004;173(9):5794–5800.
9.  Herges K et al. Neuroprotective effect of combination therapy of glatiramer acetate and epigallocatechin-3-gallate in neuroinflammation. PLoS One. 2011;6(10):e25456. Epub 2011 Oct 13.
10.Yadav V et al. Lipoic acid in multiple sclerosis; a pilot study. Mult Scler. 2005 Apr;11(2):159–165.
11.Chaudhary P et al. Lipoic acid decreases inflammation and confers neuroprotection in experimental autoimmune optic neuritis. J Neuroimmunol. 2011 Apr;233(1–2):90–96.
12.Harbige LS, Sharief MK. Polyunsaturated fatty acids in the pathogenesis and treatment of multiple sclerosis. Br J Nutr. 2007 Oct;98 Suppl 1:S46–S53.
13.Harbige LS et al. The protective effects of omega-6 fatty acids in experimental autoimmune encephalomyelitis (EAE) in relation to transforming growth factor-beta 1 (TGF-beta1) up-regulation and increased prostaglandin E2 (PGE2) production. Clin Exp Immunol. 2000 Dec;122(3):445–452.
14.Kong W, Yen JH, Ganea D. Docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen-specific Th1/Th17 differentiation and suppresses experimental autoimmune encephalomyelitis. Brain Behav Immun. 2011 Jul;25(5):872–882.
15.Shinto L et al. The effects of omega-3 Fatty acids on matrix metalloproteinase-9 production and cell migration in human immune cells: implications for multiple sclerosis. Autoimmune Dis. 2011;134592.
16.Torkildsen O et al. w-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial. Arch Neurol. 2012;69(8):1044–1051.
17.Demakova EV, Korobov VP, Lemkina LM. [Determination of gamma-aminobutyric acid concentration and activity of glutamate decarboxylase in blood serum of patients with multiple sclerosis]. Klin Lab Diagn. 2003 Apr;(4):15–17.
18.Bhat R et al. Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2580–2585.
19.Rossi S et al. Inflammation inhibits GABA transmission in multiple sclerosis. Mult Scler. Epub 2012 Mar 14.
20.Cid MP et al. Participation of the GABAergic system on the glutamate release of frontal cortex synaptosomes from Wistar rats with experimental autoimmune encephalomyelitis. Neuroscience. 2011 Aug 25;189:337–344.
21.Frigo M et al. Glutamate and multiple sclerosis. Curr Med Chem. 2012;19(9):1295–1299.
22.Barkhatova VP et al. Changes in neurotransmitters in multiple sclerosis. Neurosci Behav Physiol. 1998 Jul–Aug;28(4):341–344.

Marianne Marchese, ND
www.drmarchese.com