Anticonvulsant, anxiolytic, and cognitive protective effects of P2Y12 receptor inhibition in a pentylenetetrazol-induced epilepsy model and the potential role of the opioidergic system

Aim: Epilepsy is a neurological disorder characterized not only by recurrent seizures but also by cognitive impairment and psychiatric symptoms. The presence of treatment-resistant cases and the debilitating impact of these comorbidities underscore the need to identify novel therapeutic targets. Although P2Y12 receptors have been implicated in epilepsy, the effects of clopidogrel on seizure-associated cognitive dysfunction and anxiety, as well as the involvement of the opioidergic system, remain unknown. In this study, we investigated the effects of the P2Y12 receptor antagonist clopidogrel on seizure activity, anxiety-like behaviors, and cognitive functions in an acute pentylenetetrazol (PTZ)-induced seizure model, as well as the potential involvement of the opioidergic system in these effects. Methods: A total of 48 male Wistar albino rats were randomly allocated into six experimental groups: Control, PTZ, clopidogrel 1 mg/kg, clopidogrel 10 mg/kg, clopidogrel + nalmefene, and positive control. According to the experimental protocol, the rats received 10% DMSO, clopidogrel (1 or 10 mg/kg), nalmefene (1 mg/kg), or valproic acid (300 mg/kg) as the positive control agent via intraperitoneal administration. Thirty minutes later, PTZ (50 mg/kg, i.p.) was administered to induce seizures, whereas the control group received physiological saline. Seizure parameters were evaluated using the modified Racine scale, cognitive performance was assessed with the passive avoidance test, and anxiety-like behaviors were examined using the open field and elevated plus maze tests. Results: Clopidogrel at a dose of 10 mg/kg significantly prolonged the onset latency of myoclonic (p