Abstracts

Rationale: New approaches are essential to mitigate drug-resistant seizures. Previous results showed physical activity increased resistance to pilocarpine-induced status epilepticus and increased seizure (SZ) threshold in the 6 Hz model. A limitation of this study was that nonepileptic mice were used. Thus, we tested if voluntary running reduced seizure frequency and severity in chronic corneal kindling, a model for human partial epilepsy. Methods: Kindling was performed in male and female CF1 mice as previously reported. (Willis, S, et al. Neurobiol Dis. 2010;40(3):565-572) We tested if physical activity delayed kindling development and/or increased SZ threshold in fully kindled mice. To assess kindling development, mice were divided into two groups. Group A had free access to exercise wheels while group B mice did not. After 3 weeks of physical activity, mice received twice daily electrical stimulation following tetracaine pretreatment and seizures scored. Subsequently, kindled mice were tested for the effect of physical activity on seizure threshold using a repeated crossover experimental design. Mice were divided into two groups; one group received wheels, the other did not. After 3 weeks of physical activity, mice received 4 corneal stimuli over 2 days and the seizures were scored. In the second round, the groups were switched and SZ threshold was measured after 3 weeks. In the third round, these groups were reversed again and SZ threshold was measured 3 weeks later. Finally, the wheels were switched again and SZ threshold measured after 5 days, 13 days, and 21 days of exercise to test how quickly the exercise effect appeared or was lost. Results: Physical activity delayed kindling development in both male and female mice. Also, our results showed female mice required fewer stimulations than male mice to become fully kindled. Physical activity (PA) also modified seizure threshold in kindled mice. In each round, mice with wheels had significantly increased SZ threshold compared to sedentary (Sed) mice. That is, seizure occurrence was lower [Males, 1^st round: 50% (PA) vs 81% (Sed); 2^nd round: 70% (Sed) vs 66% (PA)], and seizure severity was lower [1^st round: 1.05 (PA) vs 3.25 (Sed);, 2^nd round: 3.2 (Sed) vs 2.0 (PA), Median SZ score on Racine scale]. These results were confirmed in a second independent experiment in males demonstrating that this is a robust effect. Female mice also benefited from physical activity as shown by similar results obtained in a third experiment. Results showed that SZ resistance developed between the 13 days and 21 days after receiving wheels and that SZ threshold became stable after 21 days of exercise. When wheels were removed seizure threshold decreased, indicating that the effect of physical activity is reversible. Conclusions: Physical activity delayed kindling development and increased SZ threshold in both male and female mice. Furthermore, the kindling results suggest sex differences in this model. Finally, this model provides a novel way to investigate the mechanism(s) behind the beneficial effects of exercise on seizures. Funding: Funding provided by the Department of Pharmaceutical Sciences, TTUHSC, Amarillo.