Anticonvulsant action of three neurosteroids against cortical epileptic afterdischarges in immature rats.

Neurosteroids exhibit anticonvulsant action probably by positive modulatory influence on GABA-A receptors. The action of three neurosteroids was tested against cortical epileptic afterdischarges in immature rats with implanted electrodes. Afterdischarges (ADs) were elicited by rhythmic electrical stimulation (biphasic pulses at 8 Hz frequency for 15s) of sensorimotor cortical region with a slightly suprathreshold current intensity. Drugs were administered intraperitoneally after the first afterdischarge and stimulation was repeated five more times with the same intensity. Allopregnanolone in doses of 20 and 30 mg/kg i.p. was found to be active in 12-day-old rats; there was no effect in 18-day-old rats and only a tendency in 25-day-old ones. Therefore, the effects of pregnanolone and a new derivative THDOC-conjugate (20 and 40 mg/kg) were compared with those of allopregnanolone (40 mg/kg) only in 12- and 25-day-old rats in the second part of study. All three neurosteroids blocked progressive prolongation of repeated ADs seen in control 12-day-old rats. In addition, pregnanolone was able to shorten the ADs. In contrast, duration of ADs in 25-day-old animals was significantly shorter than the duration of the first, predrug AD only after administration of the 40 mg/kg dose of pregnanolone; if corresponding ADs in the control and drug groups were compared, pregnanolone and THDOC-conjugate led to significantly shorter ADs, changes after allopregnanolone administration were statistically significant only in the fourth AD. None of the studied neurosteroids was able to suppress movements directly bound to stimulation as well as clonic seizures accompanying afterdischarges. Among the three drugs studied, pregnanolone was found to be the most potent one. As developmental changes are concerned, the youngest animals exhibited the highest sensitivity to anticonvulsant action of neurosteroids.