Imatinib Attenuates Pentylenetetrazole Kindled and Pilocarpine Induced Recurrent Spontaneous Seizures in Mice.

Abstract

c-Abl is a non-receptor tyrosine kinase that promotes intracellular apoptotic signaling in prolonged epileptic seizures. PTZ and pilocarpine-induced continuous epileptic convulsions cause neuronal death and gliosis. C-Abl is linked to oxidative stress, neuronal hyperexcitability, mitochondrial malfunction, and subsequent seizures. We investigated the involvement of c-Abl in epileptogenesis by employing its selective inhibitor Imatinib (1 & 3mg/kg; i.p.) together with conventional medication valproate (110mg/kg; i.p.) tends to be effective in decreasing seizures threshold provoked by PTZ for 15 days and pilocarpine for 37 days. Further, Imatinib was effective in preventing epileptic seizures arbitrated oxidative stress injury. Oxidative stress has been linked to excitotoxicity that is considered to pathogenic factor in epileptic brain damage. As ELIZA and biochemical estimations showed the high level of c-Abl as an indicator of neuronal oxidative and apoptosis under chronic PTZ & pilocarpine epileptic seizures marked by decreased antioxidants and elevated levels of caspase-3 that were successfully prevented with Imatinib treatment same as valproate (standard drug). Further, the aberrant c-Abl activation is also linked with neuroinflammation that is also predisposing factor in the development of seizures. Selective inhibition of c-Abl by Imatinib also showed anti-inflammatory activity marked with suppressed levels of NF-kB and pro-inflammatory mediators (TNF-alpha, IL-1β, and IL-6) suggesting the neuroprotective effect of Imatinib same as valproate (standard drug) in epilepsy. Therefore, the current study provides preclinical evidence of Imatinib as a potential treatment for seizures, as well as an understanding of potential role of c-Ablin epilepsy.