Coumestrol has neuroprotective effects before and after global cerebral ischemia in female rats

• Published in: Brain research 2012-09, Vol.1474, p.82-90
• Main Authors: Canal Castro, Cibele, Pagnussat, Aline S, Orlandi, Lenir, Worm, Paulo, Moura, Nathalia, Etgen, Anne M, Alexandre Netto, Carlos
• Format: Article
• Language: English
• Subjects: Animals; antagonists; Biological and medical sciences; brain; Brain Ischemia - drug therapy; Brain Ischemia - pathology; cardiac arrest; Cerebral global ischemia; Coumestrol; Coumestrol - administration & dosage; death; Delayed neuronal death; diet; Estradiol; Estradiol - administration & dosage; Estrogen Antagonists - pharmacology; estrogen receptors; Female; Hippocampus; Hippocampus - drug effects; Hippocampus - pathology; humans; Injections, Intraventricular; ischemia; Medical sciences; Neurology; neurons; Neurons - drug effects; Neurons - pathology; Neuroprotection; Neuroprotective Agents - administration & dosage; neuroprotective effect; Ovariectomy; Phytoestrogens - administration & dosage; Rats; Rats, Wistar; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2012.07.025

Abstract Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Phytoestrogens are naturally occurring plant-derived compounds that are present in the human diet and are considered selective estrogen receptor (ER) modulators. The phytoestrogen coumestrol is a potent isoflavonoid, with binding affinities for both ER-α and ER-β that are comparable to those of 17b-estradiol. The present study examined the hypothesis that coumestrol protects hippocampal neurons in ovariectomized rats in a model of cerebral global ischemia. Ovariectomized rats were subjected to global ischemia (10 min) or sham surgery and received a single intracerebroventricular or peripheral infusion of 20 μg of coumestrol, 20 μg of estradiol or vehicle 1 h before ischemia or 0 h, 3 h, 6 h or 24 h after reperfusion. Estradiol and coumestrol afforded significant neuroprotection in all times of administration, with the exception of estradiol given 24 h after the ischemic insult. Animals received icv infusion of the broad-spectrum ER antagonist ICI 182,780 (50 μg) or vehicle into the lateral ventricle just before the E2 or coumestrol administration. The ER antagonist abolished estradiol protection, consistent with a role of classical ERs. In contrast, ICI 182,780 effected only partial reversal of the neuroprotective actions of coumestrol, suggesting that other cellular mediators in addition to classical ERs may be important. Additional research is needed to determine the molecular targets mediating the neuroprotective action of coumestrol and the therapeutic potential of this phytoestrogen in the mature nervous system.