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-Converting Enzyme by a Selective Antagonist Protects Brain from Focal Ischemic Injury in Rats
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
Tumor necrosis factor 
(TNF) is an immunomodulatory and proinflammatory cytokine implicated in neuroinflammation and neuronal damage in response to cerebral ischemia. Tumor necrosis factor- converting enzyme (TACE or ADAM17) is a key sheddase that releases TNF from its inactive cell-bound precursor. Using a selective small molecule inhibitor of TACE, DPH-067517, we tested the hypothesis that inhibition of TNF 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 TNF 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.
Address correspondence to: Dr. Xinkang Wang, Department of Thrombosis Research, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543-5400. E-mail: xinkang.wang{at}bms.com
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