The effect of 2-methoxyestradiol, a HIF-1 alpha inhibitor, in global cerebral ischemia in rats.
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.
Zhou
Dachun
D
Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92350, USA.
Matchett
Gerald A
GA
Jadhav
Vikram
V
Dach
Neal
N
Zhang
John H
JH
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
D004791:Enzyme Inhibitors; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004958:Estradiol; D000077584:2-Methoxyestradiol
Life Sci. 1996;58(17):1461-7
8622572
Clin Cancer Res. 2004 Dec 15;10(24):8665-73
15623651
J Neurosci. 2005 Apr 20;25(16):4099-107
15843612
Neurol Clin. 2006 Feb;24(1):73-87, vi
16443131
Acta Neurol Scand. 1984 Jun;69(6):385-401
6464670
Stroke. 2006 Jul;37(7):1902-9
16741177
J Neurosci Methods. 2006 Dec 15;158(2):234-41
16837052
J Neurotrauma. 2002 Jan;19(1):85-98
11852981
Brain Res. 2003 Nov 14;990(1-2):20-7
14568325
J Clin Exp Neuropsychol. 2006 May;28(4):457-76
16624778