Healthy Living
Functional Therapeutics in Neurodegenerative Disease
By David Perlmutter, MD, FACN
with a Foreword by Jeffrey S. Bland, Ph.D.
Journal of Applied Nutrition, Volume 51, Number 1:3-13, 1999
(Page three of four) 1 2 3 4
The NMDA Receptor
In recognizing the importance of the NMDA receptor in the cascade ultimately leading to neuronal death, various schemes have been proposed to block the glutamate stimulation of this receptor. It has long been recognized that patients treated with Amantadine for Parkinson's disease survived longer compared to those who did not receive this medication. The specific mechanism by which Amantadine may be helpful in this regard may stem from its "neuro-protective" effect mediated through the antagonism of the NMDA receptor.19 Inhibiting glutamate stimulation of the NMDA receptor is the proposed mechanism by which gabapentin and riluzole have purported efficacy in motor neuron disease. The use of branched chain amino acids (L-leucine, L-isoleucine, and L-valine) in amyotrophic lateral sclerosis, although not having been shown to be significantly effective, was proposed as this group of amino acids is known to inhibit glutamate production. Further, excessive glutamate as a consequence of deficient clearance from the synaptic cleft may represent a specific mechanism for excessive NMDA receptor stimulation in amyotrophic lateral sclerosis.20
Nitric Oxide
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 neuro-degenerative diseases. Inhibiting its synthesis may provide an avenue for reducing the neuro-destructive capabilities of extrinsic toxins which may have implications in the neuro-degenerative 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.
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
The energy-linked excitotoxic model described above reveals multiple targets of susceptibility whereby compromised function can begin a progressive, feed-forward and thus self-perpetuating cascade ultimately culminating in neuronal death.
Functional Intervention
The energy-linked excitotoxic model described above reveals multiple targets of susceptibility whereby compromised function can begin a progressive, feed-forward and thus self-perpetuating cascade ultimately culminating in neuronal death. These include excessive glutamate leading to excessive NMDA receptor stimulation (as noted in cerebral ischemia and amyotrophic lateral sclerosis); enhanced NMDA receptor sensitivity to glutamate as a consequence of altered electro-chemical gradient due to decreased mitochondrial ATP production (as noted in idiopathic Parkinson's disease, MPTP-induced Parkinsonism, Huntington's chorea, Alzheimer's disease, and various inherited mitochondropathies); formation of NMDA receptor antibodies allowing persistent cellular inflow of calcium (noted in amyotrophic lateral sclerosis); enhanced nitric oxide production (as noted in Parkinson's disease, Alzheimer's disease, animal models, multiple sclerosis animal models, and ischemic stroke); deficiencies of small molecule antioxidants and antioxidant enzymes (Huntington's chorea, Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease); and deficiencies of xenobiotic metabolism allowing accumulation of neuro-toxic intermediates (amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease).
Inhibition of Glutamate Release/NMDA Stimulation
A number of protective agents are thought to act by inhibiting either the release of glutamate or the subsequent stimulation of the NMDA receptor. These include the anti-convulsants Neurontin, Lamotrigene, Diphenylhydantoin, Carbanazepine, and Riluzole, a pharmaceutical agent developed for the treatment of amyotrophic lateral sclerosis. Huperzine A, an ancient Chinese herbal medicine (Qian Ceng Tan), was recently described in the Journal of the American Medical Association as a possible new therapy for Alzheimer's disease. In addition to having acetylcholinesterase inhibition activity, Huperzine A specifically inhibits glutamate stimulation of the NMDA receptor.31
(Page three of four) 1 2 3 4