Dose-dependent neuroprotection by 17beta-estradiol after cardiac arrest and cardiopulmonary resuscitation.
OBJECTIVE
Despite recent advances in the treatment of cardiac arrest, neurologic outcome remains poor. 17beta-Estradiol (E2) has been widely shown to reduce damage after experimental brain injury. The present study determined whether E2 also improves neuronal survival after experimental cardiac arrest and cardiopulmonary resuscitation and if any protection is dose-dependent.


METHODS
A randomized trial.


METHODS
A research laboratory.


METHODS
Male C57Bl/6 mice weighing 20-25 g.


METHODS
Mice were randomized into one of six groups, receiving treatment with 0.5, 2.5, 12.5, 25, or 50 mug of E2 or vehicle 1.5 mins after return of spontaneous circulation. Ten minutes after induction of cardiac arrest (by KCl injection), cardiopulmonary resuscitation was initiated (with chest compressions, intravenous epinephrine, and ventilation with 100% O2). Additional animals of each E2-treated group were used for plasma estradiol-level analysis. Brains were removed for quantification of injury in the hippocampus and caudoputamen on day 3.


RESULTS
The E2 0.5 group had physiologic estrogen levels 60 min after injection (mean +/- se, 28 +/- 5 pg/mL), whereas the E2 50 group still showed supraphysiologic levels 360 min after administration (245 +/- 32 pg/mL). Hippocampal damage was not altered with E2 treatment. Only posttreatment with the lowest E2 dose (E2 0.5) resulted in attenuated neuronal injury in the rostral and caudal caudoputamen (34 +/- 11% and 27 +/- 11%), in comparison with vehicle (68 +/- 5, p < .05; 63 +/- 4%, p < .001). Higher E2 doses did not affect brain injury.


CONCLUSIONS
We conclude that E2 has a critical dosing effect on neuronal survival, physiologic levels of E2 are neuroprotective after cardiac arrest/cardiopulmonary resuscitation, and acute exposure is sufficient for brain resuscitation.
Noppens
Ruediger R
RR
Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA.
Kofler
Julia
J
Hurn
Patricia D
PD
Traystman
Richard J
RJ
D000818:Animals; D016887:Cardiopulmonary Resuscitation; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000008:administration & dosage / Q000627:therapeutic use*; D006323:Heart Arrest / Q000150:complications* / Q000628:therapy; D002534:Hypoxia, Brain / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011897:Random Allocation
D018696:Neuroprotective Agents; D004958:Estradiol