Abstract
Huntington's disease is an incurable, adult-onset, dominantly inherited neurodegenerative disease. The clinical symptoms of the disease are primarily related to the progressive death of medium spiny γ-amino butyric acid (GABAergic) neurons in the striatum and the deep layers of the cortex. Further in the later stage of life, the degeneration extends to a variety of brain regions, including the hypothalamus and hippocampus. Various GABAergic agents are being attempted for the treatment of Huntington's disease. Tiagabine [( R)- N-(4, 4-di-(3-methylthien-2-yl) but-3-enyl) nipecotic acid], a GABA uptake inhibitor, widely used in the treatment of seizures, is suggested to have neuroprotective properties. However, none of the study has elucidated its effect in the treatment of Huntington's disease and related pathologies. We explored whether tiagabine may attenuate various behavioral and biochemical alterations induced by systemic administration of 3-nitropropionic acid (an inhibitor of complex II of the electron transport chain), an accepted experimental animal model of Huntington's disease phenotype. Intraperitoneal administration of 3-nitropropionic acid (20 mg/kg., i.p.) for 4 days produced hypolocomotion, muscle incoordination and memory deficit. Daily treatment with tiagabine (5 and 10 mg/kg., i.p.) 30 min prior to 3-nitropropionic acid administration for a total of 4 days, significantly improved the 3-nitropropionic acid-induced motor and cognitive impairment. Biochemical analysis of the whole brain revealed that systemic 3-nitropropionic acid administration significantly increased lipid peroxidation, nitrite levels, total RNA levels and decreased reduced glutathione and succinate dehydrogenase activity which was reversed by daily treatment with tiagabine. Further, there was a decrease in adrenal ascorbic acid levels following daily administration of 3-nitropropionic acid, which was reversed by administration of tiagabine. The results of the present study indicate that tiagabine (5 and 10 mg/kg., i.p.) significantly reversed 3-nitropropionic acid-induced alterations in various behavioral and biochemical parameters and it could be a therapeutic agent for the treatment of Huntington's disease.
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