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The Journal of Neuroscience, September 24, 2003, 23(25):8701-8705

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BRIEF COMMUNICATION
Aromatase Cytochrome P450 and Extragonadal Estrogen Play a Role in Ischemic Neuroprotection

Louise D. McCullough,^1,2 Kathleen Blizzard,² Evan R. Simpson,³ Orhan K. Öz,⁴ and Patricia D. Hurn⁵

¹Department of Neurology and Anesthesiology and ²Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, ³Victorian Breast Cancer Consortium, Prince Henry's Institute of Medical Research, Victoria 3168, Australia, ⁴University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, and ⁵Department of Anesthesiology and Perioperative Medicine, Oregon Health Sciences University, Portland, Oregon 97239-3098

Female animals are protected from many forms of neurological injury and degeneration relative to their male counterparts, in part attributable to their native estrogens. We hypothesized that estradiol aromatized from precursor androgens via the cytochrome P450 aromatase contributes to ischemic neuroprotection in the female. Female homozygous aromatase knock-out (ArKO) mice and randomly cycling, wild-type (WT) female littermates were treated with reversible middle cerebral artery occlusion (90 min; 22 hr reperfusion). Total and regional ischemic damage was greater in female ArKOs (total, 33.5 ± 4.8%; cortical, 47.4 ± 5.7%; striatal, 44.8 ± 7.8%) compared with WT (total, 14.2 ± 5%; cortical, 14.2 ± 4.5%; striatal, 17.5 ± 8%). Baseline blood pressure and intra-ischemic cortical perfusion were comparable in knock-outs and WT, suggesting that vascular factors do not explain ArKO ischemic sensitivity. Injury was smaller in ovariectomized WT than in ArKO, emphasizing that extragonadal local estradiol plays a critical role in females. Similar increases in cortical and striatal damage were observed in female WT mice chronically treated with the aromatase inhibitor fadrozole compared with vehicle-treated control mice. Restoration of plasma 17-estradiol to physiological levels completely reversed the ArKO female's susceptibility to injury. These findings indicate that the biosynthetic enzyme P450 aromatase is key to endogenous neuroprotection in females and suggest that enhancing local, nongonadal estrogen formation could have therapeutic implications is ischemic neuropathology.

Key words: aromatase; ischemia; neuroprotection; estrogen; gender; stroke

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Received June 2, 2003; revised July 20, 2003; accepted August 4, 2003.

This article has been cited by other articles:

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