Exploration and Evaluation of Novel Pharmacological Approaches to attenuate Epileptogenesis

Abstract

Epilepsy is the second most common neurological disease with abnormal neural activity newlineinvolving various intracellular signalling transduction mechanisms. The excessive neuronal newlineactivities in the brain are associated with neurochemical changes underlying the deleterious newlineconsequences of neuronal excitotoxicity. Epilepsy is affecting 50 million people worldwide, newlinethe prevalence of occurrence is much higher in elderly patients with unpredictable and newlineuncertain neuronal changes, including degeneration of neurons, glial cells, gliosis, and newlineincreased inflammatory mediators indicating damage in the brain. Further, the alteration of newlineextracellular space-like structural changes representing shrinkage of epileptic brain encourages newlinethe present study to explore the target chondroitin sulfate as a potential target for epilepsy. newlineChondroitin sulfate (CS), as the main component of extracellular brain space, provides newlineneuronal structural support and maintains intracellular and extracellular ionic concentration. newlineTherefore, the present research work investigated the neuroprotective potential of CS, also newlinepossessing anti-inflammatory and anti-oxidant properties. The current research evaluated newlineChondroitin sulfate (CS) as a novel therapeutic agent for epilepsy (100 mg/kg and 200 mg/kg; newlinep.o.) in attenuating the kindling seizures induced by administration of sub convulsive dose of newlinePTZ (40 mg/ kg; i.p.) for 16 days in mice and pilocarpine (100 mg/kg; i.p.) induced spontaneous newlinerecurrent seizures in rodents for 37 days. Additionally, the novel pharmacological modulators newlineon chronic seizures induced neuronal excitotoxicity by using 7- Hydroxy-4-methyl-2-oxo-2Hchromene- newline8-carbaldehyde inhibitor of IRE1 (Inositol-requiring enzyme 1 ) (5 mg/kg and 10 newlinemg/kg, i.p.); c-Abl inhibitor Imatinib (1 mg/kg and 3 mg/kg, i.p.) and standard Valproate (110 newlinemg/kg, i.p.) against PTZ and pilocarpine-induced seizures in mice. Thus, the study indicated the newlineactivation of IRE-1 (Inositol-requiring enzyme 1) and c-Abl (non-receptor tyrosine kinase) under newlineprolonged seizures induced