Hormonal regulation of atypical absence seizures.
A time course study that examined the effects of the female estrous cycle on the chronic slow spike-and-wave discharges (SSWDs), gamma-aminobutyric B receptor (GABA(B)R) binding, and GABA(B)R protein expression was conducted in Long Evans hooded rats treated during development with a cholesterol synthesis inhibitor AY9944 (AY). In addition, a pharmacological study using the hormones progesterone, 17 beta-estradiol, mifepristone (intracellular progesterone receptor antagonist), tamoxifen (intracellular estrogen receptor antagonist), and allopregnanolone (progesterone metabolite) was performed to determine their effects on AY-induced seizures. The data indicate that there is a significant increase in both the duration of SSWD and GABA(B)R binding in the AY model, during the proestrus stage of the estrous cycle, the stage during which the levels of progesterone are at their highest. No changes in GABA(B)R1a or R2 protein levels were observed. In addition, the administration of both progesterone and allopregnanolone exacerbated seizures in the AY model, whereas 17 beta-estradiol attenuated the SSWD duration. Neither mifepristone nor tamoxifen blocked the effects of progesterone and 17 beta-estradiol, respectively, on SSWD duration in the AY model, suggesting that these two sex hormones are working in a manner independent of their intracellular receptors. These data suggest an important role for steroid hormones in the regulation and maintenance of AY-induced atypical absence seizures.
Institute of Medical Science, Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Vasan
V
Persad
C Guin
CG
Ting Wong
Miguel A
MA
Cortez
Yu Tian
YT
Wang
O Carter
OC
Snead
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000924:Anticholesteremic Agents / Q000633:toxicity; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000187:drug effects; D004622:Embryo, Mammalian; D004832:Epilepsy, Absence / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D030762:Estrous Cycle / Q000378:metabolism*; D005260:Female; D007839:Functional Laterality; D006728:Hormones / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D007668:Kidney; D008297:Male; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics; D011247:Pregnancy; D011485:Protein Binding; D051381:Rats; D020318:Rats, Long-Evans; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D013997:Time Factors; D014162:Transfection; D014316:Tritium / Q000493:pharmacokinetics; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000633:toxicity
D000924:Anticholesteremic Agents; D006728:Hormones; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; D014316:Tritium; C107353:CGP 54626; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride