Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase.

Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase. Research Abstract Details 

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Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase. Abstract Text:

Chandramohan Wakade,Mohammad M Khan,Liesl M De Sevilla,Quan-Guang Zhang,Virendra B Mahesh,Darrell W Brann,Chandramohan Wakade,Mohammad M Khan,Liesl M De Sevilla,Quan-Guang Zhang,Virendra B Mahesh,Darrell W Brann,

The purpose of this study was to enhance our understanding of the mechanisms of neuronal death after focal cerebral ischemia and the neuroprotective effects of tamoxifen (TMX). The phosphorylation state of 31 protein kinases/signaling proteins and superoxide anion (O(2)(-)) production in the contralateral and ipsilateral cortex was measured after permanent middle cerebral artery occlusion (pMCAO) in ovariectomized rats treated with placebo or TMX. The study revealed that pMCAO modulated the phosphorylation of a number of kinases/proteins in the penumbra at 2 h after pMCAO. Of significant interest, phospho-ERK1/2 (pERK1/2) was elevated significantly after pMCAO. TMX attenuated the elevation of pERK1/2, an effect correlated with reduced infarct size. In situ detection of O(2)(-) production showed a significant elevation at 1-2 h after pMCAO in the ischemic cortex with enhanced oxidative damage detected at 24 h. ERK activation may be downstream of free radicals, a suggestion supported by the findings that cells positive for O(2)(-) had high pERK activation and that a superoxide dismutase (SOD) mimetic, tempol, significantly attenuated pERK activation after MCAO. TMX treatment significantly reduced the MCAO-induced elevation of O(2)(-) production, oxidative damage, and proapoptotic caspase-3 activation. Additionally, pMCAO induced a significant reduction in the levels of manganese SOD (MnSOD), which scavenge O(2)(-), an effect largely prevented by TMX treatment, thus providing a potential mechanistic basis for the antioxidant effects of TMX. As a whole, these studies suggest that TMX neuroprotection may be achieved via an antioxidant mechanism that involves enhancement of primarily MnSOD levels, with a corresponding reduction of O(2)(-) production, and downstream kinase and caspase-3 activation.

Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase. Publishing Authors By Initials

C Wakade,MM Khan,LM De Sevilla,QG Zhang,VB Mahesh,DW Brann,C Wakade,MM Khan,LM De Sevilla,QG Zhang,VB Mahesh,DW Brann,

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Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Endocrinology

VOLUME: 149

Page Numbers: 367-79

Journal Abbreviation: Endocrinology

ISSN: 0013-7227

DAY: 27

MONTH: 09

YEAR: 2007

Tamoxifen neuroprotection in cerebral ischemia involves attenuation of kinase activation and superoxide production and potentiation of mitochondrial superoxide dismutase. Information

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LANGUAGE: eng

NlmUniqueID: 375040

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AFFILIATION: Professor and Associate Director, Institute of Neuroscience, Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Augusta, Georgia 30912. dbrann@mcg.edu.

Country: United States

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MEDLINETA: Endocrinology

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