Polypharmacy with tiagabine, levetiracetam, and perampanel in status epilepticus: Insights from EEG, biochemical, and histopathological studies in rats.

Abstract

Objective: Status epilepticus (SE) is a condition of neurological emergency, which precipitates various functional and morphological changes in the brain. Due to the risk of drug resistance associated with SE, this study aimed to evaluate a multitargeted approach to treat SE by combining clinically used antiseizure drugs.

Methods: In this study, we intraperitoneally administered tiagabine (TGB), levetiracetam (LEV), and perampanel (PER) alone and in combination as a duo and trio therapy after 30 min of SE in electrode-implanted male Sprague-Dawley rats subjected to lithium-pilocarpine-induced convulsive SE. The rats were monitored for SE-associated behavioral and electroencephalographic (EEG) changes. Moreover, at the end of the experiment, rats were sacrificed and brains were excised for biochemical and histopathological evaluation.

Results: The control rats showed behavioral progression to the seizure of Stages 4-5 with 30-40 min of pilocarpine administration along with the appearance of uninterrupted fully blown epileptic spikes on EEG noted up to 2 h. The rats treated with TGB, LEV, and PER alone failed to provide behavioral and ictal attenuation. However, when combinations were tested, there was an improvement in seizure presentation while TGB + PER and LEV + PER also reversed SE-associated electrographic changes. However, the most prominent seizure attenuation was noted in rats receiving trio therapy with TGB, LEV, and PER. Moreover, the trio-treated rats demonstrated marked protection from SE-induced oxidative stress and morphological alterations in different regions of the brains.

Significance: We observed that intraperitoneal administration of TGB, LEV, and PER alone did not significantly alter the ictal activity recorded by EEG but pharmacological manipulation of acutely coadministered drugs caused a reduction of electrographic, biochemical, and histopathological eruptions providing preclinical evidence of a novel multitargeted combination treatment to ameliorate the acute SE.

Plain language summary: This study investigates and compares the efficacy of mono- and polytherapy approach to counter the behavioral, electrographic, and histopathlogical manifestations of status epilepticus. The tiagabine as monotherapy was administered after 30 min of uninterrupted SE, and the outcomes were compared with levetiracetam and perampanel alone as well as their duo and trio combinations. We noted that combining the low doses of tiagabine, levetiracetam, and perampanel notably interrupted the seizure progression through distinct mechanism in rat model of status epilepticus. Thus, we conclude that this novel combination may be a promising multitargeted approach for management of status epilepticus.