1. ¹Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, Portland, Oregon, USA
2. ²Department of Anesthesiology, Johannes Gutenberg University, Mainz, Germany
3. ³Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
4. ⁴Department of Pathology, Oregon Health and Science University, Portland, Oregon, USA
5. ⁵Department of Pharmacology, University of Colorado Denver, Aurora, Colorado, USA

Correspondence: Dr RJ Traystman, Office of the Vice Chancellor for Research, University of Colorado Denver, Anschutz Medical Campus, 13001 E. 17th Place, MS F520, Building 500, Room C1000, Aurora, CO 80045, USA. E-mail: richard.traystman@ucdenver.edu

Received 10 August 2007; Revised 11 September 2008; Accepted 12 September 2008; Published online 29 October 2008.

Abstract

We evaluated long-term administration of estrogen after cardiac arrest and cardiopulmonary resuscitation (CA/CPR) on neurohistopathological and behavioral outcome. We also examined the effect of estrogen receptor (ER) stimulation using ER- agonist propyl pyrazole triol (PPT) and ER- agonist diarylpropionitrile (DPN) on neuronal survival after CA/CPR to determine whether possible neuroprotective effects of estrogen are ER-mediated. Male C57Bl/6 mice underwent 10 mins of CA/CPR and 3-day survival. In protocol 1, intravenous injection of vehicle (NaCl 0.9%) and 0.5 or 2.5 g 17-estradiol (E2 loading dose) was performed followed by subcutaneous implants containing vehicle (oil) or E2 (12.6 g), according to a treatment group. In experimental protocol 2, mice were injected (intravenously) with the ER- agonist PPT or ER- agonist DPN followed by Alzet pump implants (subcutaneously) containing PPT (200 g) or DPN (800 g). Long-term E2 administration reduced neuronal injury in the striatum after administration of either loading dose (41%19%, 35%26% of injured neurons), as compared with vehicle (68%7%, P<0.01), with no effect in the hippocampal CA1 field. In protocol 2, treatment with ER- agonist DPN reduced neuronal injury in the striatum (51%13% injured neurons) as compared with ER- agonist PPT (68%10%) and vehicle (69%11%; P<0.01). Estrogen receptor- agonist DPN reduced neuronal injury in the hippocampal CA1 field (29%22% injured neurons) as compared with ER- agonist PPT treatment (62%33%; P<0.05). Injury was not different in hippocampal CA1 between vehicle and ER- agonist-treated animals. We conclude that long-term E2 administration after CA/CPR is neuroprotective and that this effect is most likely mediated via ER-.