Hormonal regulation of seizure activity in the adult rat brain, implications for treatment of temporal lobe epilepsy

grantor: University of TorontoClinical studies suggest that gonadal steroids influence seizure activity, particularly in persons with temporal lobe epilepsy. In turn, limbic seizures may alter reproductive function. We determined the roles of gonadal hormones in altering limbic seizure thresholds and the development of motor seizures, as well as the role of limbic seizures in causing reproductive dysfunction in the adult rat. 'Methods.' Studies used both 'in vivo ' kindling of animals and 'in vitro' kindling of hippocampal slices. 'Results'. (1) Effect of hormones on seizures: In ovariectomized females, estradiol-17ß (E2) significantly lowered amygdala/seizure thresholds, facilitated amygdala and hippocampal kindling, and increased serum corticosterone levels. E2 and corticosterone, either alone or in combination, facilitated kindling. In contrast, progesterone (P4) significantly increased amygdala seizure thresholds and slowed the rate of amygdala and hippocampal kindling. P4 also suppressed stage-5 seizures in approximately 60% of intact kindled females. The anticonvulsant effects Of P4 may be receptor mediated, since treatment of epileptic hippocampal slices for 1 h with P4 and R5020 (a P4 receptor agonist), but not allopregnanolone (the P4 metabolite), significantly decreased epileptiform responses. In male rats, testosterone and its two metabolites, E2 and dihydrotestosterone, all facilitated kindling. Blockade of either androgen or E2 responses in the male significantly slowed kindling rates, as compared to intact controls. (2) Effect of seizures on reproductive function: In female rats, amygdala kindled seizures caused the cessation of estrous cycles, the development of polyfollicular ovaries, and an increase in serum E2 levels. In male rats, amygdala kindled seizures increased serum concentrations of testosterone, prolactin, and E 2, and increased testis, epididymis and pituitary weight. In contrast, generalized seizures in male rats caused a transient hypogonadal state that was restored within 6 weeks of the last seizure. 'Conclusions.' These results suggest that E2 is proconvulsive in both sexes, and that P4 receptor responses in the female are anticonvulsive. Antagonism of E2 mediated effects in the male brain and/or potentiation of progestin effects in either sex may have potential therapeutic value for men and women with temporal lobe epilepsy.Ph.D