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Research ArticleArticle

Inhibition of Tumor Necrosis Factor-α-Converting Enzyme by a Selective Antagonist Protects Brain from Focal Ischemic Injury in Rats

Xinkang Wang, Giora Z. Feuerstein, Lin Xu, Hugh Wang, William A. Schumacher, Martin L. Ogletree, Rebecca Taub, James J.-W. Duan, Carl P. Decicco and Rui-Qin Liu
Molecular Pharmacology April 2004, 65 (4) 890-896; DOI: https://doi.org/10.1124/mol.65.4.890
Xinkang Wang
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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Giora Z. Feuerstein
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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Lin Xu
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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Hugh Wang
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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William A. Schumacher
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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Martin L. Ogletree
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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Rebecca Taub
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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James J.-W. Duan
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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Carl P. Decicco
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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Rui-Qin Liu
Departments of Thrombosis Research (X.W., G.Z.F., L.X., H.W., W.A.S., M.L.O.), Neurosciences (R.A.T.), Discovery Chemistry (J.D., C.P.D.), and Inflammatory Disease Research (R.L.), Bristol-Myers Squibb Company, Princeton, New Jersey
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Abstract

Tumor necrosis factor α (TNFα) is an immunomodulatory and proinflammatory cytokine implicated in neuroinflammation and neuronal damage in response to cerebral ischemia. Tumor necrosis factor-α converting enzyme (TACE or ADAM17) is a key sheddase that releases TNFα from its inactive cell-bound precursor. Using a selective small molecule inhibitor of TACE, DPH-067517, we tested the hypothesis that inhibition of TNFα formation might have a salutary effect in ischemic stroke induced by embolic occlusion of the middle cerebral artery (MCAO). DPH-067517 selectively inhibited TACE enzyme activity in vitro (Ki = 2.8 nM), and effectively suppressed ischemia-induced increase in soluble TNFα in brain tissue after systemic administration. DPH-067517 (3 and 30 mg/kg, i.p. administered 15 min before MCAO) produced 43% (n = 8, p = 0.16) and 58% (n = 8, p < 0.05) reduction in infarct size and 36% (p < 0.05) and 23% (p < 0.05) reduction in neurological deficits, respectively. The salutary effect of DPH-067517 in ischemic brain injury was also observed when the first dose was administrated 60 min after the onset of ischemia. Inhibition of TACE had no effect on apoptosis measured by levels of active caspase-3 expression and DNA fragmentation. Our data suggest that inhibition of TACE might be a potential therapeutic strategy for neuroprotection after focal ischemic stroke.

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Molecular Pharmacology: 65 (4)
Molecular Pharmacology
Vol. 65, Issue 4
1 Apr 2004
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Research ArticleArticle

Inhibition of Tumor Necrosis Factor-α-Converting Enzyme by a Selective Antagonist Protects Brain from Focal Ischemic Injury in Rats

Xinkang Wang, Giora Z. Feuerstein, Lin Xu, Hugh Wang, William A. Schumacher, Martin L. Ogletree, Rebecca Taub, James J.-W. Duan, Carl P. Decicco and Rui-Qin Liu
Molecular Pharmacology April 1, 2004, 65 (4) 890-896; DOI: https://doi.org/10.1124/mol.65.4.890

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Research ArticleArticle

Inhibition of Tumor Necrosis Factor-α-Converting Enzyme by a Selective Antagonist Protects Brain from Focal Ischemic Injury in Rats

Xinkang Wang, Giora Z. Feuerstein, Lin Xu, Hugh Wang, William A. Schumacher, Martin L. Ogletree, Rebecca Taub, James J.-W. Duan, Carl P. Decicco and Rui-Qin Liu
Molecular Pharmacology April 1, 2004, 65 (4) 890-896; DOI: https://doi.org/10.1124/mol.65.4.890
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