Inhibition of tumor necrosis factor-alpha-converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats.
Tumor necrosis factor alpha (TNFalpha) is an immunomodulatory and proinflammatory cytokine implicated in neuroinflammation and neuronal damage in response to cerebral ischemia. Tumor necrosis factor-alpha converting enzyme (TACE or ADAM17) is a key sheddase that releases TNFalpha from its inactive cell-bound precursor. Using a selective small molecule inhibitor of TACE, DPH-067517, we tested the hypothesis that inhibition of TNFalpha 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 (K(i) = 2.8 nM), and effectively suppressed ischemia-induced increase in soluble TNFalpha 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.
Wang
Xinkang
X
Department of Thrombosis Research, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543-5400, USA. xinkang.wang@bms.com
Feuerstein
Giora Z
GZ
Xu
Lin
L
Wang
Hugh
H
Schumacher
William A
WA
Ogletree
Martin L
ML
Taub
Rebecca
R
Duan
James J-W
JJ
Decicco
Carl P
CP
Liu
Rui-Qin
RQ
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000517:prevention & control*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007511:Ischemia / Q000150:complications; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*
C483838:DPH-067517; D018696:Neuroprotective Agents; D010880:Piperidines; D011804:Quinolines; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat