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Despite the availability of anti\u2010epileptic drugs (AEDs), resistance to AEDs is the greatest challenge in treating epilepsy. The role of sphingosine\u20101\u2010phosphate\u2010receptor 1 (S1PR1) in drug\u2010resistant epilepsy is unexplored. This study investigated the effects of SEW2871, a potent S1PR1 agonist, on a phenobarbitone (PHB)\u2010resistant pentylenetetrazol (PTZ)\u2010kindled Wistar rat model. We measured the messenger ribonucleic acid (mRNA) expression of multi\u2010drug resistance 1 (MDR1) and multi\u2010drug resistance protein 5 (MRP5) as indicators for drug resistance. Rats received PHB\u2009+\u2009PTZ for 62\u2009days to develop a drug\u2010resistant epilepsy model. From day 48, SEW2871 (0.25, 0.5, 0.75\u2009mg\/kg, intraperitoneally [i.p.]) was administered for 14\u2009days. Seizure scoring, behaviour, oxidative markers like reduced glutathione, catalase, superoxide dismutase, inflammatory markers like interleukin 1 beta tumour necrosis factor alpha, interferon gamma and mRNA expression (MDR1 and MRP5) were assessed, and histopathological assessments were conducted. SEW2871 demonstrated dose\u2010dependent improvements in seizure scoring and neurobehavioral parameters with a reduction in oxidative and inflammation\u2010induced neuronal damage. The S1PR1 agonist also downregulated MDR1 and MRP5 gene expression and significantly decreased the number of dark\u2010stained pyknotic nuclei and increased cell density with neuronal rearrangement in the rat brain hippocampus. These findings suggest that SEW2871 might ameliorate epileptic symptoms by modulating drug resistance through downregulation of MDR1 and MRP5 gene expression.<\/jats:p>","DOI":"10.1111\/1440-1681.13839","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T01:54:10Z","timestamp":1705024450000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["SEW2871 reduces seizures via the sphingosine 1\u2010phosphate receptor\u20101 pathway in the pentylenetetrazol and phenobarbitone kindling model of drug\u2010refractory epilepsy"],"prefix":"10.1111","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6312-3209","authenticated-orcid":false,"given":"Ashish","family":"Jain","sequence":"first","affiliation":[{"name":"Experimental Pharmacology Laboratory, Neurobehavioral Research Laboratory, Department of Pharmacology PGIMER  Chandigarh 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