Abstract

BackgroundEpilepsy is a common neurological disorder that is characterized by recurrent episodes of seizures. Various studies have demonstrated a direct association between oxidative stress and inflammation in several neurological disorders including epilepsy. This study aimed to investigate the neuroprotective effects of a synthetic 1,3,4, oxadiazole compound A3 against pentylenetetrazole (PTZ)-induced kindling and seizure model.MethodologyPTZ was administered in a sub-convulsive dose of 40 mg/kg for 15 days, at 48-hour intervals to male Swiss-Albino mice until animals were fully kindled. Two different doses of A3 (10 mg/kg and 30 mg/kg) were administered to find out the effective dose of A3 and to further demonstrate the relative role of nuclear factor E2-related factor (Nrf2) in the PTZ-induced kindled model.ResultsOur results demonstrated a compromised antioxidant capacity associated with a low level of catalase (CAT), superoxide dismutase (SOD), glutathione (GST), and glutathione S-transferase (GSH) in the kindled group. However, the PTZ-induced group demonstrated an elevated level of lipid peroxidation (LPO) level parallel to pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), mediators as cyclooxygenase (COX-2), and nuclear factor kappa B (NFκB). Furthermore, the A3 treatment reversed these changes and overexpressed the antioxidant Nrf2 gene and its downstream HO-1. To further investigate the involvement of Nrf2, we employed an Nrf2-inhibitor, ie, all-trans retinoic acid (ATRA), that further aggravated the PTZ toxicity. Moreover, vascular endothelial growth factor (VEGF) expression was evaluated to assess the extent of BBB disruption.ConclusionThe findings of this study suggest that A3 could mediate neuroprotection possibly by activating Nrf2 dependent downregulation of inflammatory cascades.

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