Estrogen pretreatment mimics ischemic preconditioning in the brain

Ami Raval, Kunjan Dave, Ricardo Prado, Isa Saul, Raul Busto, Helen Bramlett, Miguel A. Perez-Pinzon

Research output: Contribution to journalArticle

Abstract

Background and aims: Estrogen has proven beneficial actions on neuronal survival against cerebral ischemia (1, 2). Because of promising preclinical data on neuroprotection, the Women's Estrogen for Stroke Trial was initiated. The outcomes from this trial were, however, unsuccessful and questions emerged about the safety of chronic estrogen treatment in women. In contrast to the chronic estrogen treatment strategy, our recent study demonstrated an estrogen bolus 48 h prior to ischemia induces neuroprotection in the hippocampal CA1 region in an in vitro model of organotypic slice cultures (3). Furthermore, the degree of neuroprotection induced by estrogen is similar to that achieved by ischemic preconditioning. Prompted from our in vitro study, we hypothesized that a bolus of estrogen provides pharmacological neuroprotection against ischemia in a rat model. Method: Normal cycling female rats were ovariectomized (OvX; performed at diestrus stage of estrous cycle) and 7 days later 17s-estradiol (5 or 50 μg/Kg; i.p) or vehicle (oil) was administered. Cerebral ischemia was induced in 17s-estradiol/vehicle treated rats, 48h later. Cerebral ischemia was produced by 10 min of bilateral carotid occlusion and systemic hypotension (50mmHg). Seven days after ischemia rats were fixed for histopathological assessment. Hippocampal sections at the level of 3.8 mm posterior to bregma were examined for normal neurons. Results were expressed, as mean ± SEM. Statistical significance was determined with an ANOVA test followed by a Bonferroni's post-hoc test. Results: The number of normal neurons per slice in the CA1 hippocampal region in control rats (without an ischemic episode) was 1067 ± 64 (n = 3). The ischemic insult in intact or OvX rats decreased the number of normal neurons by 87% (136 ± 9, n = 4, p < 0.05) and 88% (150 ± 10, n = 3), respectively, as compared to the control group. Interestingly, an estrogen bolus to ovariectomized rats 48h prior to cerebral ischemia increased the number of normal neurons by 39% (562 ± 116, n = 3, dose 5 μg/Kg) and 28% (450 ± 42, n = 3, dose 50 μg/Kg) as compared to ovariectomized (OvX) group (p < 0.05). Vehicle treatment did not show any significant difference in the number of normal neurons as compared to OvX groups. We also carried out a control experiment by exposing female rats to a procedure of sham-OvX. Ischemia was induced 7 days later in sham-operated females. The number of normal neurons in CA1 hippocampal region in sham-ovariectomized group did not vary from that in the OvX group, suggesting no neuroprotective effect. Conclusion: Our results demonstrate that an estrogen bolus protects the hippocampus against cerebral ischemia in a preconditioning manner. Future investigations in estrogen preconditioning may suggest new estrogen regimens that avoid potential side effects of chronic estrogen treatment for stroke patients.

Original languageEnglish (US)
Pages (from-to)BP10-01H
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue numberSUPPL. 1
StatePublished - Nov 13 2007

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ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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