Both estrogen receptor α and estrogen receptor β agonists enhance cell proliferation in the dentate gyrus of adult female rats

This study investigated the involvement of estrogen receptors α and β in estradiol-induced enhancement of hippocampal neurogenesis in the adult female rat. Subtype selective estrogen receptor agonists, propyl-pyrazole triol (estrogen receptor α agonist) and diarylpropionitrile (estrogen receptor β agonist) were examined for each receptor's contribution, individual and cooperative, for estradiol-enhanced hippocampal cell proliferation. Estradiol increases hippocampal cell proliferation within 4 h [Ormerod BK, Lee TT, Galea LA (2003) Estradiol initially enhances but subsequently suppresses (via adrenal steroids) granule cell proliferation in the dentate gyrus of adult female rats. J Neurobiol 55:247-260]. Therefore, animals received s.c. injections of estradiol (10 μg), propyl-pyrazole triol and diarylpropionitrile alone (1.25, 2.5, 5.0 mg/0.1 ml dimethylsulfoxide) or in combination (2.5 mg propyl-pyrazole triol+2.5 mg diarylpropionitrile/0.1 ml dimethylsulfoxide) and 4 h later received an i.p. injection of the cell synthesis marker, bromodeoxyuridine (200 mg/kg). Diarylpropionitrile enhanced cell proliferation at all three administered doses (1.25 mg, P<0.008; 2.5 mg, P<0.003; 5 mg, P<0.005), whereas propyl-pyrazole triol significantly increased cell proliferation (P<0.0002) only at the dose of 2.5 mg. Our results demonstrate both estrogen receptor α and estrogen receptor β are individually involved in estradiol-enhanced cell proliferation. Furthermore both estrogen receptor α and estrogen receptor β mRNA was found co-localized with Ki-67 expression in the hippocampus albeit at low levels, indicating a potential direct influence of each receptor subtype on progenitor cells and their progeny. Dual receptor activation resulted in reduced levels of cell proliferation, supporting previous studies suggesting that estrogen receptor α and estrogen receptor β may modulate each other's activity. Our results also suggest that a component of estrogen receptor-regulated cell proliferation may take place through alternative ligand and/or cell-signaling mechanisms.