Ovarian steroid modulation of seizure severity and hippocampal cell death after kainic acid treatment.
To determine whether maintained estrogen or progesterone levels affect kainic acid (KA) seizure patterns or the susceptibility of hippocampal neurons to death from seizures, ovariectomized Sprague-Dawley rats were implanted with estrogen pellets, 0.1 or 0.5 mg, that generated serum levels of 42.4 +/- 6.6 (mean +/- SEM) and 242.4 +/- 32.6 pg/ml or one to six capsules of progesterone that generated serum levels of 11.00 +/-.72 to 48.62 +/- 9.4 ng/ml. Seven days later, the rats were administered KA (8.5mg/kg, ip) and scored for seizure activity; 96 h later, the rats were killed and their brains processed for localization of neuron nuclear antigen (NeuN), a general neuronal marker. The hippocampus was scored for spread (the number of separate regions showing cell loss), and the area within the CA fields occupied by NeuN immunoreactivity was measured (indicating surviving neurons). Administration of estrogen or progesterone (independent of dose) significantly reduced mortality from KA seizures. Progesterone reduced seizure severity in animals that received one to four implants; compared with controls, no difference in seizure severity was noted for animals with six progesterone implants. The reduced seizures in progesterone-treated animals were accompanied by a reduction in the spread of hippocampal damage (r(2) = 0.87; P < 0.05). Likewise, in progesterone-treated rats, neuron survival and reduction in seizure scores were correlated (r(2) = 0.76; P < 0.0001). Estrogen had no effect on seizure severity (P > 0.05), but reduced both the spread (P < 0.05) and degree of neuronal loss (P < 0.05). Indeed, in the estrogen-treated rats, neuronal death was significantly lower than that observed in progesterone-treated animals with equally severe seizures (P < 0.05). These data are consistent with the hypothesis that progesterone produces its effects by reducing seizures, whereas estrogen has little beneficial effect on seizure behavior but protects the hippocampus from the damage seizures produce.
Hoffman
G E
GE
Anatomy and Neurobiology, University of Maryland, School of Medicine, Baltimore, MD 21201, USA. gehoffma@umaryland.edu
Moore
N
N
Fiskum
G
G
Murphy
A Z
AZ
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004343:Drug Implants; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007608:Kainic Acid; D010052:Ovariectomy; D011374:Progesterone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D012720:Severity of Illness Index; D015996:Survival Rate
D015415:Biomarkers; D004343:Drug Implants; D011374:Progesterone; D004958:Estradiol; D007608:Kainic Acid