Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat

James W. Simpkins Department of Pharmacodynamics and the Center for the Neurobiology of Aging, Departments of Neurosurgery and Pharmacology; and Center for Drug Discovery, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida

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Gopal Rajakumar Department of Pharmacodynamics and the Center for the Neurobiology of Aging, Departments of Neurosurgery and Pharmacology; and Center for Drug Discovery, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida

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Yu-Qi Zhang Department of Pharmacodynamics and the Center for the Neurobiology of Aging, Departments of Neurosurgery and Pharmacology; and Center for Drug Discovery, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida

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Christopher E. Simpkins Department of Pharmacodynamics and the Center for the Neurobiology of Aging, Departments of Neurosurgery and Pharmacology; and Center for Drug Discovery, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida

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David Greenwald Department of Pharmacodynamics and the Center for the Neurobiology of Aging, Departments of Neurosurgery and Pharmacology; and Center for Drug Discovery, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida

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Chun J. Yu Department of Pharmacodynamics and the Center for the Neurobiology of Aging, Departments of Neurosurgery and Pharmacology; and Center for Drug Discovery, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida

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Nicholas Bodor Department of Pharmacodynamics and the Center for the Neurobiology of Aging, Departments of Neurosurgery and Pharmacology; and Center for Drug Discovery, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida

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Arthur L. Day Department of Pharmacodynamics and the Center for the Neurobiology of Aging, Departments of Neurosurgery and Pharmacology; and Center for Drug Discovery, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida

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✓ The present study was undertaken to determine if estrogens protect female rats from the neurodegenerative effects of middle cerebral artery (MCA) occlusion. The rats were ovariectomized and 7 or 8 days later various estrogen preparations were administered before or after MCA occlusion. Pretreatment with 17β-estradiol (17β-E2) or a brain-targeted 17β-E2 chemical delivery system (CDS) decreased mortality from 65% in ovariectomized rats to 22% in 17β-E2—treated and 16% in 17β-E2 CDS—treated rats. This marked reduction in mortality was accompanied by a reduction in the ischemic area of the brain from 25.6 ± 5.7% in the ovariectomized rats to 9.8 ± 4% and 9.1 ± 4.2% in the 17β-E2—implanted and the 17β-E2 CDS—treated rats, respectively. Similarly, pretreatment with the presumed inactive estrogen, 17α-estradiol, reduced mortality from 36 to 0% and reduced the ischemic area by 55 to 81%. When administered 40 or 90 minutes after MCA occlusion, 17β-E2 CDS reduced the area of ischemia by 45 to 90% or 31%, respectively. In summary, the present study provides the first evidence that estrogens exert neuroprotective effects in an animal model of ischemia and suggests that estrogens may be a useful therapy to protect neurons against the neurodegenerative effects of stroke.

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