ABSTRACT Epilepsy is a chronic neurodegenerative disease characterized by recurrent and unprovoked seizures linked to neuronal hyperexcitability and network dysfunctioning. Increasing evidence proposed a pivotal relation between neuroinflammation and oxidative stress, further associated with the pathogenesis and progression of epilepsy. The present study investigates the neuroprotective effect of newly synthesized 2‐5‐ (2‐aminophenyl) ‐1, 3, 4‐oxadiazol‐2‐ylsulfanyl‐N‐ (1, 3‐benzothiazol‐2‐yl) acetamide (MA) and N‐ (1, 3‐benzothiazol‐2‐yl) ‐2‐5‐ (3‐hydroxyphenyl) ‐1, 3, 4‐oxadiazol‐2‐ylsulfanylacetamide (MS) in the pentylenetetrazol (PTZ) ‐induced chronic model of epilepsy. Mice were kindled using sub‐convulsive dose of PTZ (40 mg/kg) over 15 days. Treatment of animals with MA and MS (5, 10, and 20 mg/kg) notably reduced the number, severity and frequency of seizures in a dose‐dependent manner. Our results elaborated that MA and MS remarkably enhance glutathione (GSH), catalase (CAT) and glutathione sulfotransferase (GST) while decreased lipid peroxidation (LPO) level in MA/MS treated animal in comparison to the PTZ‐induced disease control group. MA and MS also downregulated the level of different inflammatory cytokines such as IL‐6 (interleukin‐6) and TNF‐α (Tumor necrosis factor‐α), nuclear factor kappa B (pNFκB) and upregulate the BDNF expression. Furthermore, the administration of mTOR‐inhibitor (Sirolimus) with MA and MS produced enhanced seizure suppression, suggesting a link to mTOR modulation. These results were further supported by molecular dynamic (MD) simulation studies and the protein fold expression of mTOR‐mRNA. Our findings demonstrate that MA and MS showed promising antiepileptic effect, mediated through antioxidant, anti‐inflammatory and mTOR pathway modulation. The multifaceted effects of compounds highlight them as promising neurotherapeutics lead molecules for epilepsy and related neurodegenerative disorders.
Minhas et al. (Sun,) studied this question.
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