5. The effects of progesterone, DHP, and THP on spontaneous inter ictal discharges in CA3 electrically kindled mice

Abstract

Progesterone is an anticonvulsant neurosteroid. It is reduced by the unidirectional enzyme 5 α -reductase to 5 α -dihydroprogesterone (DHP) and subsequently reduced by the bidirectional enzyme 3 α ,5 α - hydroxysteroidoxidoreductase to 3 α ,5 α -tetrahydroprogesterone (THP, also called “allopregnanolone”). Progesterone, DHP and THP have protective effects in models of traumatic brain injury, and slows epileptogenesis in kindling models. It is possible that these pregnanes could be anticonvulsant. Since anticonvulsant drugs cannot prevent epileptogenesis, endogenous hormones or their analogues remain attractive potential therapies to improve prognoses after a first seizure. In CA3-kindled aged male mice, our laboratory found high, sedative doses of progesterone, THP, and the benzodiazepine midazolam to suppress EEG afterdischarges and behavioral seizures. DHP had no anticonvulsant effect. THP and other 3 α -reduced neurosteroids are agonists for extrasynaptic GABA-A receptors with δ -subunits, which mediate most tonic inhibition in the brain. Increased tonic, GABAA δ -subunit mediated inhibition decreases IID frequency. Benzodiazepines, by contrast, target GABA-A receptors with γ -subunits, which mediate phasic inhibition in the brain. Interictal discharges (IIDs) occur spontaneously in kindled animals, and in persons with epilepsy. IIDs represent hyper-excitability of the epileptic brain, and epileptogenesis. Few studies of in vivo IIDs exist, especially outside of psychiatric research. There are no studies of IIDs in electrically kindled animals, or of the effects of pregnane neurosteroids on IIDs. We are currently investigating the effects of midazolam, progesterone, and its metabolites on IIDs. We hypothesize that progesterone, DHP, and THP may alter epileptogenic processes by reducing tonic hyper-excitability. Midazolam may alter epileptogenic processes by reducing phasic hyper-excitability. Although THP and midazolam were both effective at suppressing behavioral seizures and EEG afterdischarges, we hypothesize that IID differences will exist between progesterone, DHP, THP, and midazolam. These differences may give insight into how midazolam, progesterone, DHP and THP may alter hyper-excitability, and perhaps epileptogenesis, in the kindled mouse brain.