Poster Sessions

Neu-36

Chi-Tso Chiu

C. T. Chiu, D. M. Chuang

The beneficial effects of mood stabilizing drugs lithium and valproate in transgenic mouse models of Huntington's disease: a behavioral study

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by progressive memory loss, cognitive impairment, and emotional deterioration, in addition to movement disorder. It affects approximately 3 to 7 per 100,000 people in Western Europe and leads to death about 15 years after the initial symptom occurs. Currently, there is no proven treatment to arrest or reverse the course of HD. It has been shown that mood stabilizing drugs lithium and valproate have neuroprotective and neurotrophic effects either in vivo or in vitro, and that the neuroprotection is potentiated by co-treatment with both drugs. Therefore, the present study was designed to investigate potential beneficial effects of this co-treatment in two transgenic mouse models of HD, N171-82Q and YAC128. These two strains of mice exhibit neurological and behavioral abnormalities similar to those found in human HD patients, but have different genetic backgrounds and pathological progressions. The general motor activity and coordination of animals were measured by open-field and rotarod tests, respectively. For drug treatment, mice were fed with a control chow, or diet containing both lithium (3 g/kg) and valproate (25 g/kg) shortly before the behavioral abnormality was detected. The N171-82Q mice did not show any sign of symptoms at 6 weeks of age, but progressively exhibited poor rotarod performance in comparison with wild-type littermates. This deficit in motor coordination found in the transgenic mice measured at 14, 18, 22, and 26 weeks of age was markedly suppressed by co-treatment with lithium and valproate starting from 7 weeks of age. In addition, the drug-treated N171-82Q mice showed a significant increase in the slope obtained from the average rotarod performance across tests with 4 weeks interval, suggesting an improvement in long-term memory. In YAC128 mice, the progressive motor deficit and the decrease in the percentage of time spent in the center region of the open field, measured at 6 and 9 months of age, were also significantly inhibited by lithium-valproate co-treatment starting at 3 months of age. The latter effect of the drug co-treatment further suggested an anxiolytic benefit. Moreover, although not related to the symptoms of human HD, the heavier body weight of YAC128 mice was corrected by the treatment. Taken together, these results indicate a clinical potential of the mood stabilizing drugs lithium and valproate in treating HD patients.