Tiagabine and brivaracetam combination rewire epileptic activity in kainic acid-induced temporal lobe epilepsy model: Multimodal analysis of EEG spectra, behavior and neuroinflammatory modulation.

Abstract

Temporal lobe epilepsy is a pharmacoresistant neurological disorder associated with neurobehavioral comorbidities in which existing monotherapies prove insufficient to halt epileptogenesis and preserve neurological function. The present study investigated the antiepileptogenic and neuroprotective potential of a combination of tiagabine (TGB) and brivaracetam (BRV) in the kainic acid (KA) model of epilepsy. The BALB/c mice were intrahippocampally administered with KA, followed by treatment with TGB (3.5&#xa0;mg/kg), BRV (35&#xa0;mg/kg), or their combination for 7 days, starting 6&#xa0;h after KA injection and monitored for the incidence of electrographic changes at early chronic (4th week) and later chronic phases (12th week). The mice were tested for anxiety, cognition and depression in an array of behavioral experiments, followed by analyzing the oxidative markers, morphological changes and mRNA expression of GFAP, BDNF and TrkB in isolated hippocampi. The intrahippocampal KA administration led to epileptogenesis as mice had frequent electrographic alterations, which were accompanied by post-KA neurobehavioral disarrays, oxidative stress, neuronal degeneration and overexpression of astrocytic and neurotrophic factors. The TGB&#xa0;+&#xa0;BRV was superior to monotherapy as it mitigated pathological EEG activity and TLE-associated anxiety-like behavior and cognitive deficit and depression. Further, TGB&#xa0;+&#xa0;BRV alleviated oxidative stress (P&#xa0;<&#xa0;0.05) and increased neuronal counts (P&#xa0;<&#xa0;0.05) in CA1 and DG regions of stained hippocampi while downregulated GFAP, BDNF and TrkB. Compared to monotherapy, TGB&#xa0;+&#xa0;BRV combination offered antiepileptogenic and neuroprotective effects in the KA model. This multitargeted approach might be a beneficial disease-modifying strategy to manage pharmacoresistant epilepsy.