Toxin Models of Huntingtons Disease

Excitotoxic lesions generated in primates using NMDA receptor agonists such as quinolinic acid cause neuronal loss similar to that found in HD, emphasizing, the potential role of excitotoxicity in HD. Intrastriatal injections of the reversible succinate dehydrogenase inhibitor, malonate, into rats caused a decrease in ATP levels and increased lactate and excitotoxic lesions, which could be prevented by NMDA antagonists. 

3-nitropropionic acid (3NP), an irreversible inhibitor of succinate dehydrogenase (complex II) of the mitochondrial respiratory chain, when administered to rats or primates can also result in selective neuronal loss. In China, children exposed to 3NP from a fungal contaminant of sugar cane developed gastrointestinal disturbances followed by encephalopathy and coma, which was followed by dystonia upon recovery. In mice, 3NP caused bilateral symmetric lesions of the caudate and putamen not dissimilar to that seen with excitotoxins. When administered chronically, 3NP resulted in striatal neuronal loss, and similar to HD, NADPH diaphorase neurons were spared and in primates chronic administration produced apomorphine-inducible movement disorder involving choreiform and dystonic movements similar to HD with lesions similar to those found in HD. 

Deficiencies of complexes II and IV have been described in AD hemibrains (see Cooper and Schapira, 1997 for a review and references). 

INCREASE IN BRAIN MITOCHONDRIAL CONCENTRATIONS AND EXERTION OF NEUROPROTECTIVE EFFECTS BY COENZYME Q10 

Coenzyme Q (ubiquinone) is an essential cofactor in the electron transport chain in which it accepts electrons from complex I and II. Coenzyme Q also serves as an important antioxidant in both mitochondria I and lipid membranes. Coenzyme Q is a lipid-soluble compound composed of a redox active quinoid moiety and a hydrophobic tail. The predominant form of coenzyme Q in humans is coenzyme Q10, which contains ten isoprenoid units in the tail, whereas the predominant form in rodents is coenzyme Q9, which has nine isoprenoid units in the tail. Coenzyme Q is soluble and mobile in the hydrophobic core of the phospholipid bilayer of the inner membrane of the mitochondria in which it transfers electrons one at a time to complex III of the electron transport chain. 

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