Brivaracetam and Topiramate Co-Therapy Attenuates Seizure Progression, Neuroinflammation, and Hippocampal Pathology in Chronic Pentylenetetrazole-Kindled Mice

Abstract

Rational polytherapy is increasingly gaining attention when monotherapy fails to control seizures. Accordingly, the current study investigated the effects of topiramate and brivaracetam, administered individually (10 mg/kg each) or combined, on seizure progression alongside electroencephalographic (EEG) changes and neuroinflammatory responses in Pentylenetetrazole (PTZ)-induced kindled mice. Eleven doses of PTZ (40 mg/kg) were administered on alternate days over three weeks. Monotherapy with topiramate and brivaracetam delayed the development of generalized tonic-clonic seizures during the first week. However, it did not prevent seizures later, resulting in 80% and 60% kindled mice with 25% and 16.16% mortality, respectively. Combination therapy demonstrated 100% protection against kindling progression, with no mortality. EEG recordings revealed progressively increasing epileptiform spikes in PTZ and monotherapy-treated groups throughout the kindling period. Conversely, the combination-treated group exhibited significantly consistent reduction in epileptiform spike activity across all EEG sessions, indicating a better anticonvulsant effect. Post-kindling brain analysis revealed elevated levels of neuroinflammatory markers in the monotherapy-treated groups, while these markers were absent in the combination-treated group. RT-PCR confirmed substantial downregulation of proinflammatory and excitatory markers, including BDNF, TrkB, and TNF-α, indicating suppression of neuroinflammation and excitotoxicity in combination-treated group. Histopathological examination showed neuronal damage in the hippocampal tissues of monotherapy-treated mice, whereas no neuronal degenerations were seen in the brains of combination-treated mice. The results indicate that dual therapy with topiramate and brivaracetam provides superior neuroprotection by modulating neuroinflammatory pathways, thereby preventing seizure development and ictogenesis. These findings support the potential clinical utility of rational polytherapy in drug-resistant epilepsy.

Graphical Abstract

The figure was generated with https://www.biorender.com (LA28FJGRRL; Dated June 25, 2025).