Periodic epileptic episodes are the hallmark of epilepsy, a prevalent neurological disorder. Research suggests a significant correlation between neuroinflammation and oxidative stress in a variety of neurological diseases, such as epilepsy. A substantial amount of evidence supports the role of N-methyl-D-aspartate receptors (NMDARs) in the progression of epilepsy. Although several lines of research have disclosed numerous biochemical effects of early seizures, its connection with disturbed NMDAR/NR2B subunit expression remains unclear. 2-Mercaptobenzothiazole (MBT) is a vital scaffold with several biological activities, and its various substitutes show promising anti-inflammatory potential. The current study aimed to investigate the newly synthesized 1,3-(benzothiazole-2-sulfanyl)-1-(morpholine-4-yl)ethan-1-one (1M), a substituted MBT, for its neuroprotective potential in a mice model of pentylenetetrazole-induced epilepsy (PTZ), by modulating NMDA/NR2B pathway. The compound was tested for docking and simulation analysis, demonstrating a solid and stable bond with the NR2B subunit of NMDA. To ascertain the effects of 1M, as well as to further illustrate its mechanism of neuroprotection via NMDA/NR2B in PTZ-induced kindling model, mice of either sex were given two doses of test compound, 1M (10mg/kg and 20mg/kg). The behavioral assessments were evaluated using open-field, Y-maze, and elevated-plus maze tests, which indicated improved behavioral alterations caused by PTZ after 1M treatment. The antioxidant profiling was done by estimating glutathione-S-transferase (GST), catalase (CAT), reduced glutathione (GSH), and LPO (lipid peroxidation) in hippocampal tissues, where the test compound 1M significantly restored the depleted antioxidants, showcasing its antioxidant potential. Moreover, the cellular morphological damages induced by PTZ were detected by H&E staining, which was rescued after 1M administration. Furthermore, the activation of the inflammatory pathway was confirmed by quantitative analysis of inflammatory mediators tumor necrotic factor (TNF-α), nuclear factor kappa B (NF-κB), and cylooxegenase2 (COX-2) by enzyme-linked immunosorbent assay (ELISA), where 1M administration significantly ameliorated their expression. Furthermore, to demonstrate the involvement of the NR2B pathway, NR2B-antagonist ifenprodil was employed, and results were further confirmed through RT-PCR analysis. Our results, when considered collectively, indicate that 1M may act by inhibiting the NR2B subunit of the NMDA receptor, subsequently mitigating downstream oxidative stress and inflammatory mediators through various pathways.
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