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

The study investigated the role of neurosteroids and extrasynaptic GABA-A receptors in the antiseizure activity of midazolam using delta-subunit knockout (DKO) mice and specific blockers in the 6-Hz and hippocampus kindling seizure models. Midazolam showed rapid, dose-dependent protection against seizures in both models, and its antiseizure potency remained unchanged in DKO mice. Pretreatment with neurosteroidogenic inhibitors did not affect midazolam's efficacy, while flumazenil, a benzodiazepine antagonist, significantly reversed its effects. Plasma and brain levels of the neurosteroid allopregnanolone were not elevated in midazolam-treated animals. The findings indicated that midazolam's antiseizure activity was primarily mediated through synaptic GABA-A receptors, with no significant involvement of endogenous neurosteroids or extrasynaptic receptors.