Estrogens modulate experimentally induced apoptosis of granule cells in the adult hippocampus.
Estrogens are known to have broad effects on neuronal plasticity, but their specific role in neuronal cell death has not been determined. In the present study, we investigated the effects of beta-estradiol on an experimental model of apoptosis of granule cells of the dentate gyrus, i.e., apoptosis induced by intraventricular injection of the microtubule polymerization inhibitor colchicine. Cell death was characterized with multiple methods, including TUNEL and DNA electrophoresis. Nonrandom digestion of DNA was observed within 8-10 hours after colchicine injection, followed by condensation and fragmentation of granule cell nuclei and extensive anterograde degeneration of mossy fibers/terminals in 2 days. We compared the outcomes of the above-described manipulation in ovariectomized or sham-operated rats and animals treated daily with beta-estradiol or vehicle. Animals were lesioned with colchicine or vehicle 2 weeks after ovariectomy or sham operation. Beta-estradiol or vehicle was administered for 1 week prior to lesion and was continued for a further 2 weeks. Total numbers and densities of granule cells in different animal groups were counted by stereology in various anteroposterior levels of the hippocampus. Our results show that ovariectomy intensifies colchicine-induced granule cell apoptosis, which is ameliorated by exogenous beta-estradiol. In doses that ameliorate the adverse effect of ovariectomy, exogenous beta-estradiol appears to have no effect of preventing granule cell death in animals with intact ovaries; i.e., an estrogen excess is not more neuroprotective than physiological levels of these hormones. Taken together, our results indicate that estrogen deprivation increases the vulnerability of hippocampal neurons to injury and may predispose to neurological diseases occurring after menopause.
Liu
Z
Z
Department of Pathology (Division of Neuropathology), The Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Gastard
M
M
Verina
T
T
Bora
S
S
Mouton
P R
PR
Koliatsos
V E
VE
D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count; D003078:Colchicine; D018891:Dentate Gyrus / Q000166:cytology*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D020287:In Situ Nick-End Labeling; D008593:Menopause; D009410:Nerve Degeneration / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley / Q000502:physiology*
D018696:Neuroprotective Agents; D004958:Estradiol; D003078:Colchicine