Abstracts

Possible anticonvulsant effects of neurosteroids were studied in a model of cortical afterdischarges (ADs) in immature rats. An action of a newly synthesized derivative was compared with that of two neurosteroids (metabolites of progesterone) with repeatedly demonstrated anticonvulsant activity in adult rodents. Twelve- and 25-day-old Wistar rats were implanted with cortical stimulation and registration electrodes. To induce epileptic ADs sensorimotor region was stimulated by 15-s series of biphasic rectangular pulses with a frequency of 8 Hz. Slightly suprathreshold intensity was used for elicitation of ADs, then the drug was injected and the stimulation was repeated five more times with 10-min intervals. Two metabolites of progesterone (allopregnanolone and pregnanolone) served as a standard for testing of a new neurosteroid triethylammonium 3[alpha][ndash]hydroxy-20-oxo-5[alpha][ndash]pregnan-21-yl hydrogensuccinate (THDOC-conjugate, synthesized in the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague). The drugs were administered in doses of 20 and 40 mg/kg i.p., control siblings received saline with a drop of Tween 80. Individual age and dose groups were formed by 7-10 animals. EEG was digitalized at a rate of 500 Hz and saved on a harddisc. Motor phenomena were coded directly into the computer by an experienced observer. These activities were registered 20 s before stimulation, during stimulation and ADs and at least one min after the end of AD. Stimulation of sensorimotor cortex elicited movements of the contralateral forepaw synchronous with individual stimuli. The first stimulation always elicited an AD characterized electroencephalographically by spike-and-wave rhythm in 25- and rhythmic sharp waves in 12-day-old rat pups. These ADs were accompanied by clonic seizures of forelimb and head muscles. Control 12-day-old animals exhibited progressive prolongation of ADs with repeated stimulations. All three neurosteroids were able to block this prolongation. In addition, administration of the higher dose of pregnanolone resulted in significant shortening of ADs. Lengthening of ADs in control 25-day-old rats did not reach the level of statistical significance. The effects of neurosteroids in this age group were only moderate. Pregnanolone significantly decreased duration of ADs, but only a tendency was observed after the other two drugs. Movements directly elicited by stimulation and clonic seizures accompanying ADs remained uninfluenced by all three drugs in either age group. The new derivative THDOC-conjugate exhibited anticonvulsant action similar to allopregnanolone. In contrast, pregnanolone exhibited most potent action among the three neurosteroids tested. From developmental point of view, the younger animals were more sensitive to anticonvulsant action of neurosteroids than older rat pups. (Supported by a research project No S5011007 of the Academy of Sciences of the Czech Republic.)