Pentylenetetrazole Induced Kindling Model of Refractory Epilepsy: A Proof of Concept Study to Explore Dose and Time Range of Phenobarbital in Rats

Abstract

Purpose: Drug resistant epilepsy is an unmet medical condition that impacts 30 percent of the epileptic patients. Numerous antiseizure drugs (ASDs) have already been developed but they provide only symptomatic relief and do not target the underlying pathogenesis. Preclinical models give us the opportunities to gain insights into obscure mechanisms of Drug resistant epilepsy. Current animal models possess lacunae that need rectification and validation to discover novel antiepileptic drugs (AEDs). The present study was undertaken to validate 3 different doses of Phenobarbital (PB) at 2 different time periods. Methods: Pentylenetetrazole (PTZ) was given at sub-convulsive dose (30 mg/kg/day/i.p.) for 28 days to develop kindling in male Wistar rats. Further, kindled rats were divided into 4 groups Pentylenetetrazole control, Pentylenetetrazole and Phenobarbital (20), Pentylenetetrazole and Phenobarbital (40), Pentylenetetrazole and Phenobarbital (60) and assessed at day 14 and 28 post kindling. Seizure scoring, oxidative stress, Phenobarbital plasma levels and histopathology of hippocampal neuron were analyzed. Results: The results showed the combination of Pentylenetetrazole and Phenobarbital (40 and 60 mg/kg) remarkably decreased seizure score, elucidated higher antioxidant effect and prevent neuronal injury on day 14, whereas increased seizure score, oxidative stress and neuronal death was observed with chronic administration of Pentylenetetrazole and Phenobarbital in kindled rats at day 28. Moreover, Phenobarbital levels in blood were significantly increased at the end of day 28 of PB treatment as compared to day 14. Conclusion: The adapted protocol with Phenobarbital 40 mg/kg dose could be of great potential in screening of antiseizure drugs in refractory epilepsy.