¹Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, USA

Correspondence: Dr C Iadecola, Division of Neurobiology, Weill Medical College of Cornell University, 411 East 69th Street, Room KB410, New York, NY 10021, USA. E-mail: coi2001@med.cornell.edu

¹Current address: Department of Pharmacology, College of Medicine, Ewha Womans University, 911-1, Mok-6-Dong, Yangcheon-Gu, Seoul 158-710, Republic of Korea.

²Current address: Burke Medical Research Institute, 785 Mamaroneck Ave, White Plains, NY 10605, USA.

Received 10 May 2005; Revised 14 June 2005; Accepted 22 June 2005; Published online 27 July 2005.

Abstract

Estrogens have antiinflammatory actions and protect the brain from ischemic injury. Cerebral ischemia is accompanied by an inflammatory reaction that contributes to the tissue damage, an effect mediated in part by toxic amounts of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS). Therefore, estrogens may protect the female brain by modulating postischemic iNOS expression. To test this hypothesis, we studied whether iNOS plays a role in the mechanisms of the reduced susceptibility to ischemic injury observed in female mice. The middle cerebral artery was occluded for 20 mins using an intraluminal filament in C57Bl/6 mice, and infarct volume was assessed 3 days later in cresyl violet-stained sections. Infarcts were 53% smaller in female mice than in males (P<0.05), a reduction abolished by ovariectomy (OVX) and reinstated by estrogen replacement. In normal female mice, postischemic iNOS mRNA was lower than in males (P<0.05). Ovariectomy increased iNOS mRNA after ischemia and estrogen replacement blocked this effect. Furthermore, the iNOS inhibitor aminoguanidine reduced infarct volume in male, but not in female, mice. Similarly, male iNOS-null mice had smaller infarcts than wild-type mice, but female iNOS nulls were not protected. Ovariectomy and OVX with estrogen replacement did not affect infarct volume in iNOS-null female mice. The findings suggest that the neuroprotection conferred by estrogens is, in part, related to attenuation of iNOS expression. Such attenuation could result from the potent antiinflammatory effects of estrogens that downregulate iNOS expression via transcriptional or posttranscriptional mechanisms.