Influence of sex hormone antagonists on the anticonvulsant action of conventional antiepileptic drugs against amygdala-kindled seizures in male and female rats.
The effects of three gonadal steroid antihormones, tamoxifen (TXF, an estrogen antagonist), cyproterone acetate (CYP, an antiandrogen) and mifepristone (MIF, a progesterone antagonist) alone or combined with conventional antiepileptics were evaluated in amygdala-kindled seizures in male and female rats. None of the three antihormones used in this study affected any seizure parameter. TXF (50 mg/kg) and CYP (50 mg/kg), when combined with carbamazepine, or phenobarbital applied at their subprotective doses of 15 mg/kg, resulted in significant reductions of the seizure and afterdischarge durations, both in male and female rats. Additionally, the combination of carbamazepine and CYP markedly increased the afterdischarge threshold in fully-kindled rats of both genders. The interaction between antihormones and carbamazepine, or phenobarbital, was not reversed by respective sex steroid hormones (estradiol, testosterone). However, the TXF- and CYP-induced anticonvulsant effects in combinations with carbamazepine were attenuated by bicuculline, N-methyl-D-aspartate (NMDA) and aminophylline. Kainic acid and strychnine remained ineffective in this respect. The effect of a combination of TXF with phenobarbital was reversed by bicuculline and NMDA and that of CYP with phenobarbital-by bicuculline and aminophylline. Neither TXF nor CYP altered the free plasma concentrations of carbamazepine or phenobarbital, so a pharmacokinetic interaction is not probable. The combined treatment of the two antihormones with antiepileptic drugs did not affect motor performance, and did not result in significant long-term memory deficits. Our data confirm the hypothesis that sex hormone antagonist-mediated events may play some role in seizure processes in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs against kindled seizures.
Borowicz
Kinga K
KK
Department of Pathophysiology, Medical University, Jaczewskiego 8, 20-090, Lublin, Poland. kornel@asklepios.am.lublin.pl
Kleinrok
Zdzislaw
Z
Czuczwar
Stanisław J
SJ
D000679:Amygdala / Q000293:injuries / Q000503:physiopathology*; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D012739:Gonadal Steroid Hormones / Q000037:antagonists & inhibitors; D006727:Hormone Antagonists / Q000494:pharmacology*; D007696:Kindling, Neurologic / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D012727:Sex Characteristics
D000927:Anticonvulsants; D003292:Convulsants; D012739:Gonadal Steroid Hormones; D006727:Hormone Antagonists