Effect of GLT-1 modulator and P2X7 antagonists alone and in combination in the kindling model of epilepsy in rats

•Effect of GLT-1 modulator and P2X7 antagonist against PTZ-kindling was explored.•Functional crosstalk between P2X7 receptors and GLT-1 was elucidated.•New therapeutic strategy for epilepsy without neurotoxic and cognitive side effects

IntroductionMultiple lines of investigation have explored the role of glutamatergic and purinergic systems in epilepsy, related cognitive impairment, and oxidative stress. Glutamate transporters, particularly GLT-1 expression, were found to be decreased, and purinergic receptor, P2X7 expression, was found to be increased in brain tissue associated with epilepsy. The present study was carried out to investigate the effect of ceftriaxone (GLT-1 upregulator) and Brilliant Blue G (P2X7 antagonist) against PTZ-induced kindling in rats. The study was further extended to elucidate the cross-link between glutamatergic and purinergic pathways in epilepsy.Material and methodsSystemic administration of subconvulsant dose of PTZ (30 mg/kg) every other day for 27 days (14 injections) significantly increased the mean kindling, and developed generalized tonic-clonic seizures, and reduced motor co-ordination, cognitive skills, oxidative defense (increases lipid peroxidation, nitrite levels and decreases GSH level) and acetylcholinesterase enzyme activities in the cortex and subcortical region. Treatments with CEF (100 and 200 mg/kg) and BBG (15 and 30 mg/kg) alone and in combination (CEF 100 mg/kg and BBG 15 mg/kg) significantly decreased the mean kindling score and restored behavioral and oxidative defense activities compared with treatment with PTZ.ConclusionsThe combination of both the drugs was shown to have better effect in preventing kindled seizures and a significantly synergistic effect compared with their effect alone in PTZ-kindled rats. The present study elucidated the mechanistic role of GLT-1 modulator and selective P2X7 antagonist and their combination against PTZ-induced kindling. The study for the first time demonstrated the cross-link between glutamatergic and purinergic pathways in epilepsy treatment.