Inhibitory influence of agmatine on catamenial-like seizure susceptibility in progesterone withdrawn female rats

Abstract

Catamenial epilepsy is a condition marked by an increased occurrence of seizures that coincide with the menstrual cycle in women. Our study explored the role of neurotransmitter/neuromodulator agmatine in progesterone withdrawal induced increased seizure susceptibility that is one of the causes of catamenial epilepsy. Additionally, it investigates potential interactions between agmatine and the central neurosteroid system. The experiments involved the use of female Sprague-Dawley rats. To mime the seizure susceptibility as seen in catamenial epilepsy, rats were treated with PMSG and b-HCG which cause a higher release of progesterone and later injected with Finasteride on the 11th day of post-human chorionic gonadotropin administration to cause a sudden drop of progesterone. On the 12th day, seizure susceptibility was assessed through a low-dose (35 mg/kg) pentylenetetrazol (PTZ) injection. The results revealed that agmatine treatment showed a protective effect against seizures. Furthermore, this study explored the impact of neurosteroids such as allopregnanolone or progesterone (a precursor of allopregnanolone) and neurosteroidogenic drugs like FGIN 1–27 or metyrapone (an 11β-hydroxylase inhibitor) on the anticonvulsant effect of agmatine. The findings indicated that prior administration of these substances significantly enhanced the anticonvulsant effect of agmatine. In contrast, inhibiting neurosteroid production with drugs like trilostane (a 3β-hydroxysteroid dehydrogenase inhibitor) or indomethacin (a 3α-hydroxysteroid dehydrogenase inhibitor) completely nullified agmatine's effect. Seizures were associated with elevated progesterone levels and reduced allopregnanolone levels, which were normalized by agmatine treatment. Notably, agmatine exhibited seizure protection even in ovariectomized rats, affirming the involvement of neurosteroids in its anti-seizure effects in progesterone withdrawal increased seizure susceptibility. In conclusion, these findings emphasize central neurosteroid involvement in agmatine's pharmacological effects against seizure susceptibility in progesterone withdrawal in female rats.