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

Neuroscience. 2006 Sep 15;141(4):1793-800. doi: 10.1016/j.neuroscience.2006.05.032. Epub 2006 Jun 23.


This study investigated the involvement of estrogen receptors alpha and beta in estradiol-induced enhancement of hippocampal neurogenesis in the adult female rat. Subtype selective estrogen receptor agonists, propyl-pyrazole triol (estrogen receptor alpha agonist) and diarylpropionitrile (estrogen receptor beta 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 microg), 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 alpha and estrogen receptor beta are individually involved in estradiol-enhanced cell proliferation. Furthermore both estrogen receptor alpha and estrogen receptor beta 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 alpha and estrogen receptor beta 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.

Publication types

  • Comparative Study

MeSH terms

  • Analysis of Variance
  • Animals
  • Bromodeoxyuridine / metabolism
  • Cell Count / methods
  • Cell Proliferation / drug effects*
  • Dentate Gyrus / cytology*
  • Dose-Response Relationship, Drug
  • Doublecortin Domain Proteins
  • Estrogen Receptor alpha / agonists*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor beta / agonists*
  • Estrogen Receptor beta / genetics
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Immunohistochemistry / methods
  • In Situ Hybridization / methods
  • Ki-67 Antigen / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Neuropeptides / metabolism
  • Nitriles / pharmacology*
  • Phenols
  • Propionates / pharmacology*
  • Pyrazoles / pharmacology*
  • Rats


  • 2,3-bis(4-hydroxyphenyl)-propionitrile
  • Doublecortin Domain Proteins
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Glial Fibrillary Acidic Protein
  • Ki-67 Antigen
  • Microtubule-Associated Proteins
  • Neuropeptides
  • Nitriles
  • Phenols
  • Propionates
  • Pyrazoles
  • 4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol
  • Bromodeoxyuridine