Wang Xinkang, Feuerstein Giora Z, Xu Lin, Wang Hugh, Schumacher William A, Ogletree Martin L, Taub Rebecca, Duan James J-W, Decicco Carl P, Liu Rui-Qin
Department of Thrombosis Research, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543-5400, USA.
Mol Pharmacol. 2004 Apr;65(4):890-6. doi: 10.1124/mol.65.4.890.
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.
肿瘤坏死因子α（TNFα）是一种免疫调节和促炎细胞因子，与脑缺血后的神经炎症和神经元损伤有关。肿瘤坏死因子-α转换酶（TACE或ADAM17）是一种关键的蛋白酶，可将TNFα从其无活性的细胞结合前体中释放出来。我们使用了一种TACE的选择性小分子抑制剂DPH-067517，来检验抑制TNFα形成可能对大脑中动脉栓塞闭塞（MCAO）诱导的缺血性中风具有有益作用这一假设。DPH-067517在体外选择性抑制TACE酶活性（K(i)=2.8 nM），并在全身给药后有效抑制脑组织中缺血诱导的可溶性TNFα增加。DPH-067517（3和30 mg/kg，在MCAO前15分钟腹腔注射）分别使梗死面积减少43%（n = 8，p = 0.16）和58%（n = 8，p < 0.05），神经功能缺损分别减少36%（p < 0.05）和23%（p < 0.05）。当在缺血发作后60分钟给予第一剂时，也观察到了DPH-067517对缺血性脑损伤的有益作用。通过活性半胱天冬酶-3表达水平和DNA片段化测量，TACE的抑制对细胞凋亡没有影响。我们的数据表明，抑制TACE可能是局灶性缺血性中风后神经保护的一种潜在治疗策略。
