Supplement Therapy in Multiple Sclerosis: A Pharmacological View

Natural products, herbal medicines, and supplements have received more attention of the scientific and pharmaceutical community. Supplemental and alternative medicines include dietary supplements, herbs, vitamins, minerals, and special diets. It has been found that some complementary and alternative medicines (CAMs) are safe and effective but the important point is that less is known about many of them. Medicines used in multiple sclerosis (MS) are not completely effective and various side effects have been detected. There is an increasing trend in the use of supplementary and alternative medicines in treating MS because of fewer side effects, more comfort, and more preventative effects. It has been indicated that up to 70%-80% of people with MS have tested herbal products or bioactive compounds for treating their disease. The present study aimed to investigate the use of natural products, herbal remedies, and supplements to treat MS to confirm or rule out the effectiveness or ineffectiveness of these supplementary medicines.

disease-modifying treatments in MS patients (10). However, inadequate findings are available to make recommendations regarding their effectiveness and safety for all patients (11). The commonly used vitamin and mineral supplements with antioxidant effects include vitamin D, C, and E and selenium (12).
Various herbal medicines have been studied in the treatment of MS, which are reported as follow:

Borage seed oil (Borago officinalis)
Borage seed oil has a gamma linoleic acid content of 25% which can be regarded as a TNF-α suppressor. In addition, borage seed oil can elevate prostaglandin E (PGE) levels, which leads to an increase in cyclic adenosine monophosphate (cAMP). The point is that cAMP augmentation clarifies anti-inflammatory effects in MS treatment (13).

Blackcurrant (Ribes nigrum)
The reduction of proinflammatory mediators including tumor necrosis factor-alpha (TNF-α) and Interleukin-1β (IL-1β) in peripheral blood monocytes and antiinflammatory effects are induced by Blackcurrant seed oil in MS (14).

Bilberry (Vaccinium myrtillus)
The mechanism of bilberry in inflammatory diseases such as MS is through decreasing high-sensitivity C-reactive protein (hs-CRP), IL-12, IL-6, and Lipopolysaccharide concentrations. The anti-inflammatory effect of bilberry extract is exerted by anthocyanins. In addition, anthocyanins can improve visual impairment in MS patients (15).

Cannabis (Cannabis sativa L)
Several reports on the usefulness of cannabis in treating MS have been published. Consumption of cannabis can lead to various effects, including treatment of spasticity, improvement of tremor, reduction of depression, relief of pain, and recovery of anxiety. Both lipophilic nature and central depressant effects of cannabinoids lead to thoughts that their mechanism of action occurs via membrane disruption, similar to general anesthetics. The first cannabinoid receptor (CB1), a G-protein coupled receptor, inhibits adenylate cyclase and regulates Ca 2+ and K + channels. The receptor may also interact with other pathways, such as inositol phospholipid pathway. CNS (particularly basal ganglia, hippocampus, and cerebellum) is the main area for CB1 receptors. The inhibition of neurotransmitter release is the overall effect of CB1 receptor activation in the CNS (7).

Cat's Claw (Uncaria tomentosa)
The anti-inflammatory effect of the bark of this plant is the same as dexamethasone. Furthermore, this plant can reduce IL-4 level, while dexamethasone does not have this property. It should be noted that Cat's Claw extract can decrease PGE-2 production (16).

Dog Rose (Rosa canina)
The anti-inflammatory action of the rosehip seeds is induced by inhibition of PGE-1 which leads to the downregulatory effect on COX-1, COX-2, and leukotriene B4 (LTB 4) (18).

Evening Primrose oil (Oenothera biennis)
This oil contains sterols such as ß-sitosterol and campesterol, which have an effect on the modulators such as nitric oxide (NO), IL-1ß, TNF-α, and thromboxane B2 (TXB2), leading to the suppression of the COX-2 genome, and anti-inflammatory outcome (19).

Ginger (Zingiber officinalis)
In several investigations, it has been indicated that Ginger has immunomodulatory, anti-inflammatory, and antioxidative characteristics. Inflammation can be decreased in MS patients by Ginger via reducing the production of TNF-α and hs-CRP. Moreover, the inhibition of cyclooxygenase and lipoxygenase pathways in synovial fluid is a mechanism that leads to analgesic effects (20).

Indian Frankincense (Boswellia serrata)
The mechanism of Indian Frankincense is through the reduction of erythrocyte sedimentation rate and plasma levels of leukotriene C4, NO, and malondialdehyde. In addition, the reduction of inflammatory cytokines such as TNF-α, IL-1β, IL-6, IFN-γ, and PGE2 can be mentioned (21,22).

Olive oil (Olea europaea)
Olive oil exerts its effect through modulation and decrease of pro-inflammatory cytokines, TXB2, and leukotriene B4, leading to the reduction of inflammation in MS patients. Moreover, the reduction of lipid and protein oxidation and elevation of glutathione peroxidase can protect against oxidative damage (23).

Rosemary (Rosmarinus officinalis)
The level of inflammatory mediators such as TNF-α and IL-1ß can be reduced by rosemary extract (24). Additionally, according to an open-label trial, the use of rosemary extract reduced hs-CRP (an indicator of the presence of inflammation), indicating that rosemary is involved in reducing inflammation (25).

ussian olive or Oleaster (Elaeagnus angustifolia)
In a randomized clinical trial, a significant decrease in TNF-α and IL-10 level was observed after using Oleaster. The anti-inflammatory properties of this fruit extract can be explained by inhibition of COX-1 and COX-2 (26).

Sage (Salvia officinalis)
Carnosol and carnosic acid are two important components in chloroform extract of Salvia leaves. It has been shown that these phenolic diterpenes have anti-inflammatory effects (28) and can inhibit the production of PGE through the inhibition of microsomal PGE 2 synthase-1 (29,30).

The Stinging Nettle (Urtica dioica)
The activation of NF-κB (31) and reduction of PGD2 production can explain the anti-inflammatory effects of Urtica Dioica leaves extract. Moreover, Stinging Nettle used simultaneously with nonsteroidal anti-inflammatory drugs induces an excellent synergistic effect, with a remarkable reduction in CRP level (32).

Turmeric (Curcuma longa)
Curcumin can inhibit inflammatory proteins and cytokines. The inhibition of the differentiation of Th17 cells is noticed in a study on chronic inflammatory diseases. The importance of Th17 cells in CNS infection in patients with MS and experimental autoimmune Myasthenia gravis has been demonstrated (33). Figure 1 summarizes the effects of some of the medicinal plants in the treatment of MS.

List of the Vitamins and Supplements Used for the Treatment of Multiple Sclerosis
Vitamin B12: This vitamin is known as cobalamin and has important structural and functional roles in the CNS, and its deficiency leads to anemia, axonal degeneration, and death (34). Based on this information, fixing the deficiency of this vitamin can be effective in improving the quality of life in MS patients (33). The nature of this disease that is associated with megaloblastic and pernicious anemia along with reduced serum levels of vitamin B12 in patients with MS treated with interferon and Copaxone ® is considered in numerous studies. Moreover, the role of this vitamin in myelin repair should be noticed (34).
Vitamin D: Vitamin D can suppress the function of antigen-presenting cells which leads to a reduction in the penetration of inflammation in the CNS. The mechanism that seems to affect vitamin D nutrition in MS involves the paracrine or autocrine action of 25-hydroxyvitamin D by enzyme 1α-hydroxylase in peripheral tissues which play a role in the function of the immune and nervous system.
Optimum serum concentrations of 25-hydroxyvitamin D throughout the year may be beneficial for patients with MS, both for the removal of immune cells from disease activity as well as the reduction of disease-related complications, including increased bone turnover, fracture and muscle weakness (35).
Vitamins E and C: It has been observed that antioxidant deficiency can increase the risk of developing MS in MS patients. Indeed, antioxidants such as vitamin E (alpha-tocopherol) and vitamin C (ascorbic acid) in the MS animal models reduced the clinical symptoms of the disease. Antioxidants have the ability to reduce the symptoms of the disease by targeting specific pathogens and supporting recovery in MS (36). It should be noted that cell damage can be reduced by reducing harmful free radicals. The immune system in the nervous system can be attacked and damaged by free radicals (37).
Zinc: Numerous functions in the immune system including peripheral T-cell count, cytotoxic T-cell activity, T-helper cell function, NK-cell activity, and macrophage and neutrophil functions are influenced by zinc (Zn) deficiency (38). Zn is predominantly found in presynaptic vesicles in neurons. It is clear that effective Zn homeostasis in the brain is important (39). Increasing Zn can lead to the expression of the high-affinity receptors for IL-2, which are important for the proliferation and differentiation of CD4+ and CD8+ lymphocytes to effector cells (40).
CoQ10: CoQ10 has different mechanisms for antiinflammatory activity in MS. Among these mechanisms, the immunomodulatory properties of CoQ10 are more prominent. CoAQ10 can reduce the production of certain inflammatory mediators such as IL-6. Moreover, it can elevate antioxidant enzyme activity and diminish oxidative stress in patients with relapsing-remitting MS (41).
Polyunsaturated fatty acids: A specific deficiency of linoleic acid in the serum of MS patients has been detected by biochemical studies (42).
Omega 3, 6: The findings of a study indicated that Omega 3 and 6 have anti-inflammatory effects by reducing T-cell proliferation (43).
L-Carnitine: L-Carnitine is a natural metabolic drug that acts as a carrier molecule for long-chain fatty acids in mitochondria and generates energy. L-carnitine deficiency is associated with the accumulation of acyl CoA esters and disorders of intermediary metabolism (44). L-carnitine is reported to be effective in reducing fatigue in MS patients. It is one of the amino acid derivatives that plays an important role in the metabolism of lipids and is a key factor in mitochondrial energy production (45); therefore, it can improve fatigue in MS patients (46). Table 1 represents the effects of some supplements and medicinal plants in MS treatment.

Conclusion
Supplement therapy is regarded as a way to improve the symptoms of the disease with fewer complications for Omega-3 Results of this study indicate that omega-3 fatty acid has the ability to significantly decrease matrix metallopeptidase-9 levels and was well tolerated at a dose of 9.6 g/d over 3 months so can be effective in the process of MS improvement. patients, but health care professionals face problems in finding information regarding the usefulness of supplements. The point is that there are few scientific resources to introduce the effectiveness, mechanism, and usage of natural substances for treating the disease. In addition, receiving conventional therapies induces many side effects in MS patients. Discussing the available supplement with their usage may lead to an increasing trend in the use of CAMs in MS because of fewer side effects, more comfort, and more preventive effects.