title: The effect of 2-methoxyestradiol, a HIF-1 alpha inhibitor, in global cerebral ischemia in rats.
abstract: Global cerebral ischemia is an important clinical problem with few effective treatments. The hippocampus, which is important for memory, is especially vulnerable during global ischemia. Brain-specific knockout of hypoxia inducible factor-1 alpha (HIF-1 alpha) has been shown to be protective in focal ischemia in vivo. 2-methoxyestradiol (2ME2) is a natural metabolite of estrogen that is known to inhibit HIF-1 alpha. We tested 2ME2 in a rat model of global cerebral ischemia. Global ischemia was induced with the two-vessel occlusion model (2VO) which entailed hemorrhagic hypotension to a mean arterial pressure of 38-42 mmHg with simultaneous bilateral common carotid artery occlusion for 8 minutes. Sprague-Dawley rats (male, 280-350 g) were randomly assigned to three groups: global ischemia (GI, n=17), global ischemia with 2ME2 treatment (GI + 2ME2, n=17) and sham surgery (sham, n=12). 2ME2 treatment (15 mg/kg in 1% DMSO) was rendered 10 minutes after reperfusion. Rats in the GI and sham groups received similar doses of the DMSO solvent. Rats were killed 24 hours, 72 hours and 7 days after reperfusion. Quantitative CA1 hippocampal cell counts demonstrated significantly lower cell survival in the GI + 2ME2 group compared to either the GI or sham groups, in spite of a statistically significant reduction in HIF-1 alpha by Western blotting analysis of the GI + 2ME2 group. We conclude that 2ME2 worsens outcomes after global ischemia in rats.
authors: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92350, USA.
authors: Dachun
authors: D
authors: Zhou
authors: Gerald A
authors: GA
authors: Matchett
authors: Vikram
authors: V
authors: Jadhav
authors: Neal
authors: N
authors: Dach
authors: John H
authors: JH
authors: Zhang
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004958:Estradiol; D000077584:2-Methoxyestradiol
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