Moderate-intensity treadmill exercise improved the anticonvulsant efficacy of topiramate and attenuated anxiety and depressive-like side effects in epileptic rats by upregulating 5-HT1A receptors in the hippocampus and cerebral cortex.

BACKGROUND

Topiramate (TPM) is a broad-spectrum antiseizure medication associated with dose-limited mood-related adverse effects, including depression, which significantly impair patient quality of life and treatment adherence. Although physical exercise confers neuroprotective and mood-stabilizing benefits, its potential to counteract TPM-induced behavioral deficits and the underlying neurobiological mechanisms, particularly within the serotonergic system, remains largely unexplored.

OBJECTIVE

The present study investigated whether exercise reduced the effective dose of topiramate and attenuates its depressive-like side effects in epileptic rats.

METHODS

Male Wistar rats were randomly assigned to nine groups (n = 10/group): Sham, Seizure, Exercise (EX), TPM (25 mg), TPM (50 mg), TPM (70 mg), EX + TPM (25 mg), EX + TPM (50 mg), and EX + TPM (70 mg).The exercise protocol consisted of treadmill running (30 min/day, 5 days/week for 4 weeks). Seizure severity and latency were assessed using the Racine scale. Depressive-like behaviors and anxiety were evaluated by the Tail Suspension Test (TST) and the Elevated Plus Maze (EPM). Immunohistochemistry was performed to quantify 5-HT1A receptor immunoreactive staining intensity in the hippocampal CA1, CA3, and cerebral cortex.

RESULTS

Combination therapy (EX+TPM (50 mg) and EX + TPM (70 mg)) demonstrated superior anticonvulsant effects, significantly reducing seizure scores and prolonging seizure latency compared to TPM monotherapy (p < 0.001). TPM monotherapy dose-dependently exacerbated depressive-like behaviors (e.g., increased immobility in the TPM (70 mg) group, p < 0.001). Crucially, exercise attenuated these adverse effects in all EX + TPM groups. 5-HT1A receptor expression was significantly downregulated in the Seizure and TPM (25 mg) groups compared with the Sham and Exercise groups. In contrast, the EX + TPM (50 mg) and EX + TPM (70 mg) groups showed significant upregulation of 5-HT1A receptors in the hippocampus and cerebral cortex (p < 0.001).

CONCLUSION

The current findings demonstrate that adjunctive moderate-intensity treadmill exercise potentiates the anticonvulsant efficacy of topiramate and effectively counteracts its depressive-like side effects and anxiety. This behavioral improvement was correlated with exercise-mediated upregulation of 5-HT1A receptors, suggesting a potential mechanistic link. These findings provide a preclinical rationale for further investigation into the potential benefits of exercise as an adjunctive therapy in epilepsy, though clinical translation requires additional studies.