Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice
Liqun Zhang, … , Ian A. Simpson, Susan J. Vannucci
Liqun Zhang, … , Ian A. Simpson, Susan J. Vannucci
Published January 1, 2004
Citation Information: J Clin Invest. 2004;113(1):85-95. https://doi.org/10.1172/JCI18336.
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Categories: Article Metabolism

Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice

Abstract

Diabetic hyperglycemia increases ischemic brain damage in experimental animals and humans. The mechanisms are unclear but may involve enhanced apoptosis in penumbral regions. Estrogen is an established neuroprotectant in experimental stroke. Our previous study demonstrated that female diabetic db/db mice suffered less damage following cerebral hypoxia-ischemia (H/I) than male db/db mice. Here we investigated the effects of diabetes and estrogen apoptotic gene expression following H/I. Female db/db and nondiabetic (+/?) mice were ovariectomized (OVX) and treated with estrogen or vehicle prior to H/I; brains were analyzed for damage and bcl-2 family gene expression. OVX increased ischemic damage in +/? mice; estrogen reduced tissue injury and enhanced antiapoptotic gene expression (bcl-2 and bfl-1). db/db mice demonstrated more damage, without increased bcl-2 mRNA; bfl-1 expression appeared at 48 hours of recovery associated with infarction. To our knowledge, this is the first description of bfl-1 in the brain with localization to microglia and macrophages. Early induction of bfl-1 expression in +/? mouse brain was associated with microglia; delayed bfl-1 expression in diabetic brain was in macrophages bordering the infarct. Furthermore, estrogen replacement stimulated early postischemic expression of bcl-2 and bfl-1 and reduced damage in normoglycemic animals but failed to protect the diabetic brain.

Authors

Liqun Zhang, Aji Nair, Kyle Krady, Christopher Corpe, Robert H. Bonneau, Ian A. Simpson, Susan J. Vannucci

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Figure 1

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Evolution of hypoxic-ischemic damage in +/? and db/db mice: effect of es...
Evolution of hypoxic-ischemic damage in +/? and db/db mice: effect of estrogen. Female +/? and db/db mice were subjected to bilateral ovariectomy at 5 weeks of age and received 5 μg estradiol intraperitoneally in sesame oil (OVX+E), or 5 μg vehicle (OVX), daily for 12 days prior to H/I. All mice were subjected to unilateral H/I for 20 minutes as described in Methods and sacrificed at recovery intervals from 8 hours to 120 hours (5 days). Four 2-mm brain sections were frozen and 16-μm cryosections were cut before isolation of RNA for subsequent analysis (Figures 2–4). Sections were stained with H&E, and infarct fraction was calculated as a percentage of the contralateral hemisphere, as described in Methods. Bars represent mean infarct fraction ± SD for four to six mice per group for nondiabetic +/? (a) and db/db (b). *Significant effect of estrogen replacement, P < 0.05. Values for db/db OVX+E at 48 hours to 5 days were not different from one another and, when combined, were significantly greater than values at 24 hours (P < 0.05).