Introduction

Epilepsy is a chronic neurological disorder characterized by sustained disruptions in neuronal excitability, leading to spontaneous and recurrent seizures that reflect abnormal, synchronized neural circuit activity (Du et al., 2026). These epileptiform discharges impair physiological communication between the cerebral cortex and subcortical regions, resulting in transient impairments in behavior, motor function, and cognition (Dahal et al., 2019). Current clinical guidelines establish pharmacotherapy as the principal intervention for epilepsy, with the primary objective of achieving seizure suppression (Tomson et al., 2023). A fundamental mechanism of action for many antiseizure drugs involves restoring neurochemical equilibrium by enhancing GABA-mediated inhibition and/or reducing glutamatergic excitation (Sears and Hewett, 2021). Topiramate, a broad-spectrum antiseizure medication, modulates neuronal excitability through three primary mechanisms: blockade of voltage-gated sodium and calcium channels, and enhancement of GABAergic activity (Bai et al., 2022). Despite its favorable pharmacodynamic profile, mood disturbances, including depression and suicidal ideation, have been reported as adverse effects. These side effects are primarily attributed to excessive inhibition of glutamatergic neurotransmission, specifically via blockade of AMPA and kainate receptors. Additionally, topiramate may contribute to mild central nervous system metabolic acidosis through the inhibition of carbonic anhydrase. It has been proposed that the drug may indirectly elicit depressive-like symptoms by modulating dopaminergic and serotonergic pathways; however, the precise mechanisms underlying these effects remained to be fully elucidated (Hudon and Proulx, 2022, Soleimani Meigoni et al., 2022).

Physical exercise is increasingly recognized as a non-pharmacological strategy that confers neuroprotective and mood-stabilizing benefits in individuals with epilepsy (Tero-Vescan et al., 2025). Aerobic exercise enhances serotonergic neurotransmission through multiple pathways, including increased tryptophan bioavailability, elevated serotonin synthesis, and adaptive changes in receptor expression. These changes include region-specific modulation of 5-HT1A receptors, downregulation of inhibitory somatodendritic autoreceptors in the raphe nuclei, and upregulation of excitatory postsynaptic receptors in target regions such as the hippocampus and cerebral cortex (Heijnen et al., 2016, Sha et al., 2026).

Accumulating evidence from preclinical and clinical studies underscores the role of regular physical activity in modulating neuronal excitability and conferring seizure protection. The underlying mechanisms are multifactorial and include enhanced neuroplasticity, facilitated by the upregulation of brain-derived neurotrophic factor (BDNF). This neuroplastic adaptation is accompanied by reinforcement of inhibitory GABAergic neurotransmission and stabilization of synaptic homeostasis (Ebrahimnezhad et al., 2023, Ambrogini et al., 2023).

Mood disorders, particularly depression, are highly prevalent among patients with epilepsy. Physical exercise exerts profound therapeutic effects on mood regulation and affective disorders. Its efficacy in ameliorating depressive-like and anxiety-related behaviors is mediated through several interconnected neurobiological pathways. Exercise modulates monoaminergic systems, including serotonin, norepinephrine, and dopamine (Pietrelli et al., 2018, Zhang et al., 2022, Albert et al., 1999). Regular physical activity attenuates neuroinflammation by downregulating pro-inflammatory cytokines such as IL-1β and TNF-α, a mechanism linked to the pathophysiology of depression (Xiao et al., 2021, Brás et al., 2022). Aerobic exercise promotes hippocampal neurogenesis, thereby counteracting the hippocampal atrophy frequently observed in mood disorders (Vints et al., 2024).

Despite the advent of newer-generation antiseizure medications, topiramate remains an indispensable therapeutic agent for a distinct subset of patients with drug-resistant epilepsy (Deng et al., 2025).

Clinical evidence and pharmacogenetic insights suggested that, for certain individuals, topiramate is uniquely capable of establishing effective seizure control. Furthermore, inter-individual variability in pharmacokinetics, pharmacodynamics, and polymorphisms affecting drug targets and neural circuits may render topiramate the most effective option for a patient’s specific seizure fingerprint. Consequently, in contemporary epilepsy management, topiramate is often regarded as an essential rescue therapy for patients who have proven refractory to multiple first and second-line treatment regimens. Nevertheless, despite its well-established antiseizure efficacy, the clinical utility of topiramate is limited by neuropsychiatric adverse effects, most notably depression and suicidal ideation.

Despite substantial evidence supporting the beneficial effects of exercise on brain function and its anti-inflammatory properties, as well as the well-documented side effects of topiramate, no study has yet investigated whether exercise can mitigate the adverse psychiatric effects of topiramate while maintaining or enhancing its anticonvulsant efficacy. Specifically, the role of 5-HT1A receptor modulation in this interaction has remained unexplored. Given the high comorbidity of depression and epilepsy, identifying a non-pharmacological strategy to improve the therapeutic profile of AEDs could have significant clinical implications.

Therefore, the present study was designed to address the following research question: Does moderate-intensity aerobic exercise enhance the anticonvulsant efficacy of topiramate while attenuating its depressive-like side effects in a PTZ-induced seizure model, and if so, is this effect associated with changes in 5-HT1A receptor expression?

We hypothesized that exercise would reduce the effective dose of topiramate and prevent the reduction of 5-HT1A receptor expression, thereby improving both seizure control and mood-related outcomes. To test this hypothesis, we investigated the effect of moderate-intensity treadmill exercise on the anticonvulsant efficacy of topiramate as well as its depressive-like side effects in a rat model of PTZ-kindling. In addition, the 5-HT1A receptor expression in the hippocampus and cerebral cortex as the possible involved mechanism was assessed.