Neuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity

Yonghua Zhang, Dejan Milatovic, Michael Aschner, Paul J. Feustel, Harold K. Kimelberg

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

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 ∼ 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 F2-IsoPs and F4 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).

Original languageEnglish (US)
Pages (from-to)819-827
Number of pages9
JournalExperimental Neurology
Volume204
Issue number2
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

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Keywords

  • Behavior
  • ICI 182,780
  • Infarct volume
  • Isoprostanes
  • Male Sprague-Dawley rats
  • Middle cerebral artery occlusion
  • Neuroprostanes

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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