Role of Neurosteroidogenic Pathways in the Antiseizure Activity of Midazolam in the 6‐Hz and Kindling Models of Epilepsy

Abstract

Midazolam is a benzodiazepine anticonvulsant with rapid onset of action. Midazolam is used for controlling acute seizures and status epilepticus. The antiseizure activity of midazolam is thought to be due to its allosteric potentiation of synaptic GABA-A receptors. There are indications that benzodiazepines promote endogenous neurosteroid synthesis via the 18kDa cholesterol transporter protein (TSPO). Thus, we investigated the role of neurosteroids and their extrasynaptic GABA-A receptor targets in the antiseizure activity of midazolam. Here, we used delta-subunit knockout (DKO) mice to investigate the contribution of the extrasynaptic receptors to the antiseizure activity of midazolam. The protective activity of midazolam was examined using specific blockers in the 6-Hz and hippocampus kindling seizure models. In both models, midazolam produced a rapid and dose-dependent protection against seizures. The antiseizure potency of midazolam was undiminished in DKO mice. Pretreatment with neurosteroidogenic inhibitors PK11195 and finasteride did not affect the antiseizure effect of midazolam. It was significantly reversed by flumazenil, a benzodiazepine antagonist. Plasma and brain levels of the neurosteroid allopregnanolone were not greater in midazolam-treated animals. These studies demonstrate that endogenous neurosteroids and extrasynaptic receptors are not involved in the antiseizure activity of midazolam, which mainly occurs through synaptic GABA-A receptors.