Vegan Health ArticlesAlzheimer's Disease: Functional Therapeutics in Neurodegenerative Disease
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Nitric Oxide

By David Perlmutter, M.D.

As described above, nitric oxide (NO) seems to play a pivotal role in the cascade of events leading to neuronal death following glutamate stimulation of the NMDA receptor. Nitric oxide is formed when L-arginine is oxidized to citrulline by the action of the enzyme nitric oxide synthase. Although nitric oxide itself is a free radical due to its unpaired electron, it is not felt to participate in any significantly damaging chemical reactions in and of itself. However, when reacting with superoxide anion, the extremely reactant and potent oxidant peroxynitrite (ONOO) is formed. This reaction is approximately three times faster than the reaction dismutating superoxide to form hydrogen peroxide catalyzed by superoxide dismutase (SOD).[21] Peroxynitrite has been implicated in a variety of damaging intra-neuronal events including DNA strand breaks, DNA deamination, nitration of proteins including superoxide dismutase, damage to mitochondrial complex I, complex II, and mitochondrial aconitase. In addition, nitric oxide itself also specifically damages mitochondrial complex I.[22]

Thus, nitric oxide physiology has been a central focus of research in the neurodegenerative diseases. Inhibiting its synthesis may provide an avenue for reducing the neuro-destructive capabilities of extrinsic toxins which may have implications in the neurodegenerative disorders, if in fact extrinsic toxins (or even endogenously produced toxins) participate in chronic expression of nitric oxide synthase. The role of nitric oxide in the pathogenesis of Parkinson’s disease is exciting and remains the focus of vigorous research. Hantraye and associates in Orsay, France published research in 1996 demonstrating that pre-treatment of baboons with the nitric oxide synthase inhibitor 7-nitroindazole (7-NI) completely prevented the induction of Parkinsonism in baboons exposed to MPTP. These researchers demonstrated that inhibiting nitric oxide synthase “protected against profound striatal dopamine depletion and loss of tyrosine hydroxylase-positive neurons in the substantia nigra” and “protected against MPTP-induced motor and frontal-type cognitive deficits.”[23]

Elevated levels of nitric oxide synthase have been found in the brains of patients with multiple sclerosis. Bagasra and colleagues at Thomas Jefferson University demonstrated elevated levels of nitric oxide synthase messenger RNA in 100% of the CNS tissues from seven multiple sclerosis patients, but in none of three normal brains. The authors conclude, “These results demonstrate that NOS, one of the enzymes responsible for the production of nitric oxide, is expressed at significant levels in the brains of patients with MS and may contribute to the pathology associated with the disease.”[24]

Nitric oxide may also play an important role in the pathogenesis of Alzheimer’s disease. Beta-amyloid plaques are a characteristic histopathological finding in Alzheimer’s disease. When cultured rat microglia are exposed to beta-amyloid, there is a prominent microglial release of nitric oxide especially in the presence of gamma- interferon.[25] In cortical neuronal cultures, treatment with nitric oxide synthase inhibitors provides neuro-protection against toxicity elicited by human beta-amyloid.[26]

The role of nitric oxide in mediating neuronal damage in cerebral ischemia is also the subject of intense research. Again, the operative model recognizes excessive glutamate stimulation of the NMDA receptor in cerebral ischemia with elevation of intracellular calcium and induction of nitric oxide synthase raising intra-neuronal nitric oxide. In addition, elevated cytosolic calcium converts the enzyme xanthine dehydrogenase to xanthine oxidase which results in excessive superoxide anion formation, thus setting the stage for the production of the highly reactive peroxy-nitrite radical (ONOO-) via the mechanism described above. Transgenic mice over-expressing SOD with resultant decreased superoxide formation are protected against focal ischemia, as are mice which genetically lack nitric oxide synthase.[27]

Because of the wide-ranging implications of nitric oxide chemistry in both acute and chronic neuro-destructive entities, selected inhibition of nitric oxide synthase has become the focus of extensive pharmaceutical research. Specific attempts to inhibit nitric oxide synthase include the use of arginine analogues, which compete with L-arginine for catalytic binding sites on nitric oxide synthase. Arginine analogues, however, are associated with profound cerebral vaso-constriction and thus may result in worsening perfusion.[28]

Nutritional approaches focusing on increased dietary citrulline may offer an alternative approach to reducing nitric oxide formation. As noted by Larrick, “Although citrulline is not one of the amino acid building blocks of protein, large quantities of free citrulline do occur in some foods such as watermelon, Citrullus vulgaris, which contains 100 mg/100 grams.”[29]

Substituted guanidoamines may demonstrate therapeutic promise through the mechanism of inhibition of nitric oxide synthase, especially in multiple sclerosis. In auto-immune encephalomyelitis in mice (an animal model for multiple sclerosis), aminoguanidine, an inhibitor of nitric oxide synthase, when administered to mice sensitized to develop experimental auto-immune encephalomyelitis, specifically inhibited disease expression in a dose-related manner.[30]

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We began this archive as a means of assisting our visitors in answering many of their health and diet questions, and in encouraging them to take a pro-active part in their own health. We believe the articles and information contained herein are true, but are not presenting them as advice. We, personally, have found that a whole food vegan diet has helped our own health, and simply wish to share with others the things we have found. Each of us must make our own decisions, for it's our own body. If you have a health problem, see your own physician.