Abstract

1. Medicinal Mushroom Preparations as Functional Food for Multiple Sclerosis: A Review Skylar Saveland; David Porter, PhD; Edward Novey, MD; John Holliday, PhD BioRevival, a Non-Profit Corporation, Marietta, GA Abstract Multiple Sclerosis (MS) is a devastating autoimmune demyelinating disease of the central nervous system for which there is no cure. Because the approved medications offer only a modest benefit, are very expensive, and often have unbearable side-effects, many patients seek to influence the course of their disease using diet, supplements, or unapproved therapies. Evidence indicating that edible mushrooms have great potential to help maintain health and ameliorate illness is rapidly emerging. The scientific literature has been reviewed; a few medicinal mushrooms are leading candidates for further MS research: species of the genus Hericium, including Hericium erinaceus, species of the genus Cordyceps, including Cordyceps sinensis, Cordyceps militaris, Cordyceps ophioglossoides, and Cordyceps pruinosa, Ganoderma species including Ganoderma lucidum and Ganoderma tsugae, and Poria cocos. Not all medicinal mushrooms can be recommended to those who suffer from MS; some may be detrimental to the MS patient by over-stimulating the immune system. Impetuous consumption of any and all medicinal mushrooms is not advisable. A scientific rationale exists for these species. The proposed mechanisms of actions are: the induction of neurotrophic factors such as nerve growth factor (NGF), direct neurotrophic action of pharmacologically active constituents, prevention of neuronal apoptosis, improvement in noradrenergic functioning in the locus coeruleus system, catecholamine modulation, cholinergic action, cyclooxygenase (Cox-1/Cox-2) inhibition, modulation of cytokine expression, competition with myelin autoantigens on immune cell receptor sites, non-steroidal anti-inflammatory action, pro-steroidal endocrine modulation, antimicrobial action (viral and bacterial microbes may contribute to Multiple Sclerosis manifestation as co-factors or even as the sole cause of MS[i][ii][iii][iv][v]), sedative, analgesic and anti-nociceptive action, improvement in intestinal flora, improvements in cardiovascular, hepatic, and renal functioning, antioxidant status, supplementation of conditionally essential saccharides (CESs), and increasing the overall sense of health and well-being. Because of the pervasive use of alternative therapies by those who suffer from MS and marketing campaigns promoting the use of preparations of questionable efficacy, an aggressive research program is warranted, in order to further assess the potency of a medicinal mushroom preparation as a treatment for Multiple Sclerosis. Anecdotal reports of significant relief of symptoms and relapses further indicate the need for comprehensive scientific analysis. Poria cocos (Indian Tuckahoe)‏ Poriatin, derived from Poria cocos (Pc), reduced the severity of EAE.[i] Poria is commonly prescribed in Asia for autoimmune diseases and is said to ameliorate these conditions by upregulating IL-10 and suppressing Th-1 overactivity.[ii]Pc demonstrated significant immune-supressing activity in a heart transplant model.[iii] Antioxidant activity suppressed free-radical-induced cytolysis.[iv]Poria markedly inhibits HIV-1.[v] A traditional Asian preparation containing Pc reduced immune-mediated inflammation in cultured astrocytes.[vi] Another Korean mixture containing Pc also displayed neuroprotective effects[vii] and rescued neurons from nitric oxide induced damage, preventing the accumulation of disability.[viii] A different traditional preparation of Pc and two other traditional Chinese medicines demonstrated neuroprotective effects, in vitro and in vivo, reducing the production of NO and preserving cognitive function in distinct animal models of neurological damage.[ix] Another mixture containing P. cocos significantly inhibited cyclooxygenase-mediated inflammation.[x] Cyclooxygenase (Cox-1/Cox-2) inflammation has recently been implicated in neurodegeneration.[xi][xii] Traditional Korean herbs used to protect the brain were screened to assess the different anti-cholinesterase activities of each. P. cocos demonstrated 27.8% inhibition in the model.[xiii] Cholinergic intervention has demonstrated great potential in the development of future MS therapeutics.[xiv] The reputed ability of P. cocos to improve cognition was supported by another experimental model.[xv] Poria may benefit individuals with MS through immune-modulation and multiple forms of neuro-protection. Cordyceps sinensis, C. militaris, C. ophioglossoides, and C. pruinosa Cordyceps sinensis (Cs) may be able to alter the course of various kinds of autoimmune diseases by muting immune over-response to lipopolysaccharide (LPS).[i] Relapse in MS models can be induced by introducing LPS into the spinal cord, causing an inflammatory cascade.[ii][iii] Anti-inflammatory and antinociceptive activities, and related antioxidant, anti-angiogenic, and nitric oxide (NO) inhibiting activities of C. sinensis and C. militaris have been demonstrated.[iv][v] Data show that Cs has been effective in lupus models[vi][vii] and human trials.[viii] Interferon-β, the reference drug for MS, may benefit lupus patients, as well.[ix] Though marketed as an agent that can ‘boost’ immune response, Cs has shown great potential for producing immunosuppressive agents[x] and possibly ameliorating diseases like autoimmune nephropathy.[xi]Cs has potential as an immunoceutical for the treatment of Th-1 mediated autoimmune diseases,[xii] of which MS is a member.[xiii] Cs is widely used as a dietary supplement to increase strength and endurance. However, in competitive male cyclists, no appreciable improvement was found.[xiv] Positive effects on endurance, fatigue and objective stress measures have been recorded in experimental models.[xv][xvi] In addition to increasing endurance, researchers have noted an anti-inflammatory effect.[xvii] Researchers who assume the clinical effectiveness of C. sinensis in relieving fatigue and increasing endurance, in the elderly, offer data showing increases in hepatic adenosine triphosphate levels.[xviii] Many believe that C. sinensis may not confer much benefit in increasing the strength and endurance of those who are near peak conditioning, but greatly benefits the chronically fatigued.[xix] This belief is apparently supported by a randomized, double-blind, placebo-controlled clinical trial that has not been published in English.[xx] Subjective improvements in mood and energy are often felt by the consumer. Cs stimulates corticosteroid production, in vitro,[xxi] and in vivo.[xxii] Corticosteroids, possessing substantial anti-inflammatory and immunosuppressive activity, are approved for the treatment of relapsing/remitting MS. Production of other endogenous steroids appears to be increased by Cs as well.[xxiii] The Cordyceps genus is a known source of anti-viral,[xxiv][xxv] antibacterial,[xxvi] and immune-modulating compounds that hold promise for future discovery of therapeutic agents.[xxvii] Cyclosporine, the reference immune-suppressing drug for transplant surgery, is derived from the anamorph of C. subsessilis.[xxviii]The potential beneficial actions of C. sinensis are immune-modulating, immune-suppressing, pro-steroidal, non-steroidal anti-inflammatory, anti-oxidant, anti-fatigue, and anti-microbial. Improvement in hepatic and renal functioning may also be of note. Cordyceps ophioglossoides (Co) prevented neuronal cell death in in vitro and in vivo models of amyloid-beta induced damage.[xxix] The role of amyloid in MS, damaging the actual axons and causing the accumulation of disability, has been well described.[xxx][xxxi]C. ophioglossoides also contains a novel anti-fungal agent, ophiocordin.[xxxii]Co is not as well studied as other species of medicinal mushrooms. Co may exert actions on many different systems. At this time, the proposed action of Co is neuro-specific antioxidation, preventing amyloid-beta induced damage. A methanol extract of Cordyceps pruinosa inhibited important inflammatory mediators of Multiple Sclerosis in vitro and in vivo: IL-β, TNF-α, NO, prostaglandin, Cox-2, and NF-κB.[xxxiii] This finding, though preliminary and solitary, offers great hope for the future amelioration of Multiple Sclerosis. Ganoderma lucidum (Reishi, Ling Zhi) & Ganoderma tsugae Ganoderma lucidum (Gl) has been shown to inhibit forms of inflammation that are implicated in MS such as inducible nitric oxide synthase (iNOS)[i][ii] and histamine,[iii] and has immune-modulating effects including the promotion of interleukin-10 (IL-10) expression.[iv] IL-10 upregulation is an approach to MS and other autoimmune conditions.[v]Ganoderma tsugae alleviated immune-mediated inflammation in an allergic asthma model.[vi]A protein (LZ-8) from Gl suppressed autoimmune disease in an animal model,[vii] showing extraordinary immunosuppressive potential comparable to prednisolone and cyclosporine without toxic effects.[viii] Prednisone, a prednisolone precursor, approved for use in remitting/relapsing MS because of the desired immunosuppressive and anti-inflammatory action, has important side-effects. Gl demonstrated neuroprotective potential by dramatically suppressing apoptosis of PC12 cells.[ix]Ganoderma species have unique immune-modulating, immune-suppressing and neuroprotective potential that may be significant for MS treatment. Hericium erinaceus (Yamabushitake, Hou Tou, Pom Pom, Lion’s Mane)‏ Hericium erinaceus (He) produces molecules, known as the erinacines, which have been shown to be strong inducers of NGF, in vitro.[i] Intra-cerebral NGF infusion significantly reduced the manifestation of experimental autoimmune encephalomyelitis (EAE) in a primate model.[ii] Erinacine A was confirmed as a strong inducer of NGF, in vivo, with some specificity toward the locus coeruleus, a system that can further neurotrophic activity, in a secondary manner, and induce other neurotrophic factors such as NT-3. Interestingly, catecholamine production was significantly induced by the compound, indicating great potential for the relief of Parkinson’s and other neurological disorders as well.[iii] The noradrenergic locus coeruleus/lateral tegmentum system influences the functioning of large areas of the brain and spinal cord and has been successfully targeted as a means to ameliorate Multiple Sclerosis.[iv]H. erinaceus extract promoted myelination with no toxic effects, in vitro. Myelination was faster and began earlier than the controls, while normal development was otherwise maintained.[v] An exo-polysaccharide, derived from He, chemically unrelated to the erinacines, was found to promote adrenal neurite growth, differentiation, and arborization more rapidly and with greater potency than brain-derived nerve factor (BDNF) or NGF. Neuronal apoptosis was drastically reduced (from 50% to 20%) by the polymer, as well.[vi] Whole He was found to be safe and effective against Alzheimer’s dementia in Japanese clinical trials.[vii] Anti-microbial activities of He have been demonstrated. A novel laccase was isolated from He mushroom with inhibitory activity toward HIV-1 reverse transcriptase.[viii] Herical, another derivative of He, inhibits a large spectrum of bacteria and fungi.[ix] Cases of methicillin-resistant Staphylococcus aureus in humans were cured during a Japanese clinical trial evaluating the merit of He as a therapeutic agent for Alzheimer’s dementia. The anti-MRSA compounds were subsequently identified as two of the erinacines.[x]In vitro, Hericium has a sedative effect on hippocampal neurons with no toxic effect, apparently supporting the researcher’s view that H. erinaceus is promising for the treatment of diseases such as MS, Alzheimer’s, etc.[xi] Erinacine E has been declared a kappa opioid agonist with analgesic potential.[xii] Thus, the main proposed actions of Hericium erinaceus are neurotrophic, antiapoptotic, adrenergic, catecholaminergic, antimicrobial, sedative and analgesic. Other beneficial effects may include antioxidation, hepatoprotection, and immune-modulation. Hericium also contains important compounds that incorporate xylose, galactose, fucose, and other CESs. Conclusions Much remains to be learned about MS and future therapeutic interventions. There is certainly reason to believe that dietary supplementation of these traditional products can benefit the MS patient. However, further understanding of the active constituents, optimum dosage, production styles, media construction, growth parameters, and the distinct phases of the fungal lifecycle producing unique molecules is necessary to ascertain whether ingesting a preparation of full-spectrum, unrefined natural product is objectively and markedly useful in reducing the symptoms and inhibiting the progression of Multiple Sclerosis. Second generation products such as extracts or synthetic derivatives may prove advantageous. Photos courtesy of: Hericium erinaceus, David Porter; Cordyceps, clockwise from upper left: unremembered species, David Porter; C. ophioglossoides, Northwest Alliance for Computational Science and Engineering; C. militaris,juana@micologia.net; C. pruinosa, Japanese Cordyceps Society; Ganoderma, David Porter; Ganoderma lucidum, George Barron; Poria cocos, David Porter; Cordyceps sinensis, special thanks to earthgrown.net.