Neuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity.
We have previously shown that tamoxifen can induce marked neuroprotection after middle cerebral artery occlusion (MCAo) in rats and have described two possible mechanisms of action: namely, inhibition of EAA release and inhibition of nNOS activity. In this study we tested other potential mechanisms. Namely, agonist action at estrogen receptors and an antioxidative action. Tamoxifen-treated rats had significantly improved neurobehavioral deficit scores after 24 h and showed approximately 75% reduced infarct volumes. These were unaffected by ICI 182,780 (a high affinity and pure receptor antagonist) administered intravenously, or intracisternally to avoid possible lack of brain penetration, 15 min before intravenous administration of tamoxifen. In rats subjected to 2 h MCAo followed by 22 h reperfusion, 1.8-fold and 2.9-fold increases of F(2)-IsoPs and F(4) neuroprostanes, respectively, as relatively stable markers of oxidative damage, were measured in the ischemic hemisphere compared with the corresponding contralateral hemisphere or sham controls. Tamoxifen given at 3 h after the start of ischemia reduced the IsoPs and NeuroPs to sham control levels, and also inhibited their production by chemically induced lipid peroxidation in brain homogenates. These data are consistent with at least part of tamoxifen's marked neuroprotection in focal cerebral ischemic injury being due to its antioxidant activity but not by an acute action on estrogen receptors (212 words).
Zhang
Yonghua
Y
Neural and Vascular Biology Theme, Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA.
Milatovic
Dejan
D
Aschner
Michael
M
Feustel
Paul J
PJ
Kimelberg
Harold K
HK
D000578:Amidines / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D004965:Estrogen Antagonists / Q000008:administration & dosage; D028441:F2-Isoprostanes / Q000378:metabolism; D000077267:Fulvestrant; D007839:Functional Laterality; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000502:physiology*; D013629:Tamoxifen / Q000627:therapeutic use*
D000578:Amidines; D000975:Antioxidants; D004965:Estrogen Antagonists; D028441:F2-Isoprostanes; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D004281:Docosahexaenoic Acids; D004958:Estradiol; C046728:2,2'-azobis(2-amidinopropane)