Category: Preclinical Development
Purpose: New approaches are essential to mitigate drug-resistant seizures. We previously showed that physical activity delayed kindling development in the corneal kindling model. A limitation of this study was only male mice were used. Therefore, using both male and female mice simultaneously, we tested if voluntary running delayed kindling development in chronic corneal kindling, a model for human partial epilepsy.
Methods: Kindling refers to repeated electrical or chemical stimuli, which ultimately reduces the seizure (SZ) threshold and causes seizures. In corneal kindling model, mice receive twice daily electrical stimulation through eyes following tetracaine treatment for two to three weeks. The mouse is fully kindled when it demonstrates 4 consecutive stage 4 or 5 seizures, the severe form of seizures. Once mice are fully kindled, the electrical stimuli are discontinued. For non-kindled mice, electrical stimuli are continued for two to three weeks. Mice with lower SZ threshold require a smaller number of stimulations to be fully kindled than mice with higher SZ threshold. Kindling was performed in male and female CF1 mice as previously reported. (Willis, S, et al. Neurobiol Dis. 20 10;40(3):565-572) To assess kindling development, mice were divided into four groups, group A (exercise male), group B (sedentary male), group C (exercise female), group D (sedentary female). Group A and group C had free access to exercise wheels while group B and group D mice did not. After 3 weeks of physical activity, kindling was conducted for 3 weeks and seizures scored.
Results: Physical activity delayed kindling development. The average number of stimulations required to be fully kindled was larger in exercise mice than sedentary mice in both male mice [group A: 36.75, group B: 25.45] and female mice [group C: 32.14, group D: 22.44] (Figure 1). Furthermore, the percentage of fully kindled mice were significantly lower in exercise mice than sedentary mice in both male mice [group A: 40% (4/10), group B: 82.5% (33/40)] and female mice [group C: 70% (7/10), group D: 90% (36/40)] (Figure 2). When the comparison was made for exercise groups (group A vs group C) and sedentary groups (group B vs group D), female mice required fewer stimulations than male mice in both exercise groups and sedentary groups in a stepwise progression of corneal kindling, suggesting sex differences in this model (Figure 3).
Conclusion: Physical activity delayed kindling development. This result confirms the reproducibility of the previous experiment that has also demonstrated delaying kindling development in exercise mice. Furthermore, the anticonvulsant effect of physical activity is more evident in male mice than female mice, suggesting the sex difference in this model. Future studies will be directed to investigate the metabolic and biochemical mechanism(s) behind the beneficial effects of exercise on seizures and to assess sex differences in corneal kindling.