Schielke G P, Yang G Y, Shivers B D, Betz A L
Department of Neurological and Neurodegenerative Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan, USA.
J Cereb Blood Flow Metab. 1998 Feb;18(2):180-5. doi: 10.1097/00004647-199802000-00009.
A variety of recent studies suggest a role for both inflammatory cytokines such as interleukin-1 beta (IL-1 beta), and apoptosis in ischemic brain injury. Because IL-1 beta converting enzyme (ICE) is required for the conversion of proIL-1 beta to its biologically active form, and has homology with proteins that regulate apoptosis in invertebrates, we studied the effect of cerebral ischemia on brain injury in mutant mice deficient in the ICE gene (ICE knockout [KO] mice). Focal cerebral ischemia, produced by occlusion of the middle cerebral artery, resulted in brain edema (increased water and sodium content) at 4 hours and a histologically defined brain lesion at 24 hours. Both of these markers of brain injury were significantly reduced in the ICE KO mice as compared to wild-type C57BL/6 mice. Regional cerebral blood flow, determined using the flow tracer, N-isopropyl [methyl 1,3-(14)C] p-iodoamphetamine (14C-IMP), was similar in the two strains of mice, indicating that the reduced brain injury in the KO mice was not a result of a lesser degree of ischemia. These data show that ICE contributes to the development of ischemic brain damage, and that it plays a role at an early time in the pathologic process. Although the mechanism of this effect is uncertain, our results suggest that pharmacologic inhibition of ICE may be a useful treatment for stroke.
最近的一系列研究表明，诸如白细胞介素-1β（IL-1β）等炎性细胞因子以及细胞凋亡在缺血性脑损伤中都发挥了作用。由于IL-1β转换酶（ICE）是将前体IL-1β转化为其生物活性形式所必需的，并且与调节无脊椎动物细胞凋亡的蛋白质具有同源性，因此我们研究了脑缺血对ICE基因缺陷的突变小鼠（ICE基因敲除[KO]小鼠）脑损伤的影响。通过大脑中动脉闭塞产生的局灶性脑缺血，在4小时时导致脑水肿（水和钠含量增加），并在24小时时导致组织学上明确的脑损伤。与野生型C57BL/6小鼠相比，ICE KO小鼠的这两种脑损伤标志物均显著降低。使用血流示踪剂N-异丙基[甲基1,3-(14)C]对碘安非他明（14C-IMP）测定的局部脑血流量在两种小鼠品系中相似，表明KO小鼠脑损伤减轻并非缺血程度较轻所致。这些数据表明，ICE促成了缺血性脑损伤的发展，并且在病理过程的早期发挥作用。尽管这种作用的机制尚不确定，但我们的结果表明，对ICE的药物抑制可能是治疗中风的一种有效方法。
