Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury
Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury
复制标题
DOI：
10.1172/jci2169
复制
发表时间：
1998-05-01
影响因子：
15.9
通讯作者：
Holtzman, DM
中科院分区：
文献类型：
--
作者：
Cheng, Y;Deshmukh, M;Holtzman, DM
细胞程序性死亡(细胞凋亡)是发育中的神经系统的正常过程。最近的数据表明，程序性细胞死亡过程中的某些特征可能更有利于发育中的大脑，而不是成年人的大脑，以应对不同的脑损伤。在一个特征性的新生儿缺氧缺血模型中，我们显示了显著的但延迟的细胞死亡，其中有明显的DNA梯状、TUNEL标记，以及带有浓缩染色质的细胞核。在许多细胞凋亡性死亡的情况下，caspase激活是必需的，在缺氧缺血后也遵循延迟的时间进程。脑缺血后3h侧脑室注射半胱氨酸氨基转移酶抑制剂BOC-天冬氨酸(OME)-氟甲基酮具有明显的神经保护作用。此外，全身注射BOC-天冬氨酸(OME)-氟甲基酮也是以延迟的方式进行，导致了显著的神经保护。这些发现表明，在发育中的大脑发生缺氧缺血事件后，caspase抑制剂可能能够在延长的治疗窗口内提供益处，这是静止性脑病和脑性瘫痪的主要诱因。
Programmed cell death (apoptosis) is a normal process in the developing nervous system. Recent data suggest that certain features seen in the process of programmed cell death may be favored in the developing versus the adult brain in response to different brain injuries. In a well characterized model of neonatal hypoxia-ischemia, we demonstrate marked but delayed cell death in which there is prominent DNA laddering, TUNEL-labeling, and nuclei with condensed chromatin. Caspase activation, which is required in many cases of apoptotic cell death, also followed a delayed time course after hypoxia-ischemia. Administration of boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, was significantly neuroprotective when given by intracerebroventricular injection 3 h after cerebral hypoxia-ischemia. In addition, systemic injections of boc-aspartyl(OMe)-fluoromethylketone also given in a delayed fashion, resulted in significant neuroprotection. These findings suggest that caspase inhibitors may be able to provide benefit over a prolonged therapeutic window after hypoxic-ischemic events in the developing brain, a major contributor to static encephalopathy and cerebral palsy.