veggies.jpg (6769 bytes)fruitbowl.jpg (6391 bytes)Alzheimer's Disease: Functional Therapeutics in Neurodegenerative Disease
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Alzheimer's Disease: Functional Therapeutics in Neurodegenerative Disease
David Perlmutter, M.D.

www.pcrm.org

Mitochondrial Dysfunction

The direct clinical consequences of mitochondrial dysfunction in specific diseases have long been appreciated. The clinical manifestation of specific types of mitochondrial pathology are well understood in such syndromes as Kearn-Sayre syndrome (KSS), Leberís hereditary optic neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), chronic progressive external ophthalmoplegia (CPEO), Luftís disease, and others. In these diseases, specific mitochondrial DNA abnormalities and consequent abnormalities of the mitochondrial respiratory chain activity have been well delineated. It is now recognized, however, that acquired mitochondrial DNA abnormalities can also set the stage for significant clinical manifestations. Oxidative damage to mitochondrial DNA has been estimated to be 10-fold higher than damage to nuclear DNA.[1] It has been estimated that mitochondrial DNA mutation rate may be 17 times higher compared to nuclear DNA.[2] These findings are not surprising in that mitochondrial DNA is located in close proximity to the inner mitochondrial membrane which is the site of greatest cellular production of reactive oxygen species (ROS). Further, unlike nuclear DNA, mitochondrial DNA lack significant DNA repair mechanisms.[3]

It is now known that several important neurodegenerative conditions are characterized by defects of mitochondrial function. In Parkinsonís disease, it has been estimated that there is a 35% deficiency of complex I in the substantia nigra.[4] Deficiencies of cytochrome oxidase (complex IV) activity in the cerebral cortex as well as platelets of Alzheimerís disease have been reported.[5]

The importance of decreased efficiency of mitochondrial oxidative phosphorylation activity is multi-factorial. Perhaps the most important consequence of inefficient energy production is a change in the neuronal transmembrane potential. Under normal conditions, with adequate mitochondrial energy production, a normal trans-membrane potential exists. The transmembrane potential has a profound effect on the activity of a specific receptor for the excitatory neurotransmitter glutamate. This receptor (NMDA receptor) under normal conditions of transmembrane electrochemical gradient (normal mitochondrial ATP production) is functionally blocked by magnesium ion. When mitochondrial oxidative phosphorylation activity becomes depressed, alterations in the transmembrane potential relieve the magnesium block of the NMDA receptor which, when stimulated by the excitatory neurotransmitter glutamate, causes influx of calcium into the cytosol.

It is the influx of calcium into the cell which plays a pivotal role in the cascade of events leading to neuronal destruction including activation of nitric oxide synthase, increased mitochondrial free-radical production, and activation of proteases and lipases.

It is interesting to note that in Parkinsonís disease, Huntingtonís disease, and Alzheimerís disease, mitochondrial dysfunction leading to excessive free-radical production and oxidative tissue damage seems to be confined to the brain despite the fact that the underlying mitochondrial abnormality is systemic. Indeed, mitochondrial defects in platelets in Parkinsonís disease (50% deficiency in complex I activity) have been well described.[6] This may be explained by the unique susceptibility of the brain to mitochondrial dysfunction and resultant excessive free-radical production since the brain uses approximately 20% of the total O2 consumption (while representing only 1/50th of the body weight). Thus, being so highly metabolic, brain tissue generates more oxyradicals. Second, neurons are post-mitotic. This allows accumulation of oxidatively damaged DNA, proteins, and lipids compared to cells which retain the property to undergo mitosis. Third, compared to other highly metabolic tissues, the brain has relatively low levels of protectant antioxidant enzymes and small-molecule antioxidants.[7]

It has long been known that there is a significant relationship between previous xenobiotic exposure and the risk of various neurodegenerative diseases including Alzheimerís disease, Parkinsonís disease, and amyotrophic lateral sclerosis. As reported by Semchuk in 1992, ďConsistently having a history of occupational herbicide use resulted in a significant increased Parkinsonís disease risk of about three fold Ö.Ē[8]

If indeed mitochondrial dysfunction plays an important role in the pathogenesis of neurodegenerative diseases and the various studies indicating increased risk with xenobiotic exposure are valid, what mechanism could relate these two concepts? The answer to this question may have been provided in a report by Davis et al. in 1979.[9] This report described the production of a Parkinsonian syndrome in humans exposed to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyradine), an analog of Meperidine. It was subsequently found that MPTP administered to various animals, predominantly primates, would likewise produce a syndrome mimicking human Parkinsonís disease. Further, animals treated in this manner were found to be responsive to typical anti-Parkinsonian medications. The discovery of MPTP provided valuable information, which has a direct bearing on the understanding of the etiology of Parkinsonís disease. First, it has been discovered that MPTP is a specific direct inhibitor of complex I of the electron transport chain.[10] Inhibition of complex I causes depletion of ATP production, altering the neuronal trans-membrane gradient rendering the NMDA receptor more receptive to glutamate. The resulting influx of calcium enhances reactive oxygen species generation which further damages mitochondrial activity in a self-propagating feed-forward cycle, ultimately leading to cell death. The importance of NMDA receptor sensitivity as a link in this destructive chain is exemplified by the work of Tursky who demonstrated that blocking the NMDA receptor with specific antagonists would prevent damage to the substantia nigra in experimental animals exposed to MPTP.[11] Further, it appears that nitric oxide plays a pivotal role in the toxicity to substantia nigra neurons induced by MPTP. Mice pre-treated with 7-nitroindazole, a nitric oxide synthase inhibitor, demonstrate a dose-dependent protection against MPTP substantia nigra damage.[12] This implies that nitric oxide formation also plays an important role with respect to free-radical neuronal damage induced by mitochondrial energy production dysfunction. Clarification of the mechanism of neuronal injury whereby MPTP is metabolized to reactive MPP+, which is then selectively transported across the neuronal membrane by specific dopamine transporters leading to mitochondrial damage, has encouraged researchers to identify other exogenous or endogenous chemicals which may act in a similar fashion.

Recently, Dr. Manfred Gerlach published research identifying N-methyl-(R)-salsolinol as a possible endogenous MPTP-like neuro-toxin.[13] The possibility that xenobiotics may act in a fashion similar to MPTP, coupled with the obvious link of Parkinsonís disease risk with pesticide exposure, has encouraged research specifically focused on the role of xenobiotics as toxic agents with respect to mitochondrial function. In a study reported by Flemming et al., Dieldrin, a lipid-soluble long-lasting mitochondrial toxic pesticide, was found in six of twenty brains of Parkinsonís patients and in none of controls.[14]

But what appears as perhaps an obvious question with respect to the increased risk of Parkinsonís in individuals exposed to pesticides is why some of those exposed will manifest the disease while most will not. Could some individuals manifest dysfunction of xenobiotic metabolism to the extent that toxic metabolites are not cleared appropriately and thus remain within the body, ultimately inflicting damage on delicate neuronal homeostatic mechanisms? The answer to this question has perhaps best been answered by Steventon and others who have demonstrated significant abnormalities of xenobiotic metabolism in Alzheimerís disease, Parkinsonís disease, motor neuron disease, and even rheumatoid arthritis.[15,16] The specific abnormalities of detoxification described by these authors involve decreased activity of phase II sulfation. Phase I abnormalities including the P450 enzymes IID6 and cysteine dioxygenase have also been described.[17] Identification of ďat riskĒ individuals, i.e., those individuals with inherited hepatic detoxification flaws, may allow the development of preventive strategies to reduce the likelihood of disease manifestation. Specific evaluation of hepatic detoxification pathways is now widely available.[18]

References

Go on to: The NMDA Receptor
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