Antiseizure Effects of Mirtazapine in a Rat Model of Status Epilepticus Via Cannabinoid Receptor Modulation

Abstract

Status epilepticus (SE) is a severe neurological condition with high morbidity and mortality rates. Despite the availability of treatments, many cases remain refractory to standard therapies. In this study we investigated the possible anticonvulsant effects of mirtazapine in SE-induced rats, and further examined the underlying mechanisms contributing to its observed neuroprotective properties. Male Wistar rats were subjected to SE and pre-treated with different doses of mirtazapine (3, 10, 30, 50 mg/kg). Seizure severity using Racine’s scale and latency of first seizure were assessed. The involvement of cannabinoid receptors was examined using AM-630, a CB2 antagonist (0.5 mg/kg). Diazepam (1 mg/kg), a GABA_A positive allosteric modulator, was co-administered with mirtazapine to assess potential involvement of GABA receptors in mirtazapine’s effects. The effects of K_ATP channel modulation were studied using glibenclamide (3 mg/kg), a K_ATP channel blocker. Additionally, CB1 receptor and indoleamine-2,3-dioxygenase (IDO) expression levels were measured using western blotting. Also, effects of mirtazapine were assessed when administered after SE induction, both alone (3 and 30 mg/kg) and in combination with diazepam (1 mg/kg). Pre-treatment with mirtazapine at doses of 30 and 50 mg/kg significantly reduced seizure severity and increased the latency to the first seizure, indicating a dose-dependent anticonvulsant effect. The anticonvulsant effects were mediated through the activation of CB1 and CB2 receptors, as evidenced by inhibition of these effects by sub-effective dose of AM-630 and upregulation of CB1 receptor expression following mirtazapine treatment. Co-administration of sub-effective doses of diazepam and mirtazapine significantly increased the latency to seizures but did not reduce the SE severity score. Additionally, sub-effective dose of glibenclamide inhibited only the mirtazapine’s effects in increasing the latency to seizures but not its reducing of seizure severity. IDO expression remained unchanged, suggesting that the kynurenine pathway may not play a significant role in mirtazapine’s anticonvulsant effects in SE. Of note, Mirtazapine either alone or in combination with sub-effective doses of diazepam, did not affect seizures when administrated after SE induction. This study shows that only pre-treatment with mirtazapine can effectively prevent SE primarily through the activation of CB1 and CB2 cannabinoid receptors. Further studies, including clinical trials, are needed to validate these findings.