doi: 10.1161/01.STR.0000030317.43597.C8
(Stroke. 2002;33:2485.)
© 2002 American Heart Association, Inc.
Original Contributions |
Neuroprotective Effects of a Novel Non–Receptor-Binding Estrogen Analogue
In Vitro and In Vivo Analysis
From the Department of Pharmacology and Neuroscience, Health Science Center at Fort Worth, University of North Texas (R.L., S-H.Y., E.P., K.D., J.W.S.); Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville (E.P., K.E., K.P-T.); Department of Statistics, College of Medicine, University of Florida, and Veterans Affairs Rehabilitation Outcomes Research Center for Excellence, Gainesville, Fla (S.S.W.); Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville (L.P.); Department of Neurosurgery, College of Medicine, University of Florida, Gainesville (A.L.D.); and Department of Molecular Biology and Pharmacology, School of Medicine, Washington University, St Louis, Mo (Z.Y.C., D.F.C.).
Correspondence to Dr James W. Simpkins, Department of Pharmacology and Neuroscience, Health Science Center at Fort Worth, University of North Texas, 3500 Camp Bowie Blvd, Fort Worth, TX 76107. E-mail jsimpkin{at}hsc.unt.edu
Background and Purpose— Although estrogens are neuroprotective, hormonal effects limit their clinical application. Estrogen analogues with neuroprotective function but lacking hormonal properties would be more attractive. The present study was undertaken to determine the neuroprotective effects of a novel 2-adamantyl estrogen analogue, ZYC3.
Methods— Cytotoxicity was induced in HT-22 cells by 10 mmol/L glutamate. 17ß-Estradiol (E2) or ZYC3 was added immediately before the exposure to glutamate. Cell viability was determined by calcein assay. The binding of E2 and ZYC3 to human 
(ER) and ß (ERß) estrogen receptors was determined by ligand competition binding assay. Ischemia/reperfusion injury was induced by temporary middle cerebral artery occlusion (MCAO). E2 or ZYC3 (100 µg/kg) was administered 2 hours or immediately before MCAO, respectively. Infarct volume was determined by 2,3,5-triphenyltetrazolium chloride staining. Cerebral blood flow was recorded during and within 30 minutes after MCAO by a hydrogen clearance method.
Results— ZYC3 significantly decreased toxicity of glutamate with a potency 10-fold that of E2. ZYC3 did not bind to either ER or ERß. Infarct volume was significantly reduced to 122.4±17.6 and 83.1±19.3 mm3 in E2 and ZYC3 groups, respectively, compared with 252.6±15.6 mm3 in the ovariectomized group. During MCAO, both E2 and ZYC3 significantly increased cerebral blood flow in the nonischemic side, while no significant differences were found in the ischemic side. However, E2 and ZYC3 significantly increased cerebral blood flow in both sides within 30 minutes after reperfusion.
Conclusions— Our study shows that ZYC3, a non–receptor-binding estrogen analogue, possesses both neuroprotective and vasoactive effects, which offers the possibility of clinical application for stroke without the side effects of estrogens. It also suggests that both the neuroprotective and vasoactive effects of estrogen are receptor independent.
Key Words: cerebral blood flow • estrogens • ischemia • neuroprotection • receptors, estrogen • reperfusion injury
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