Himi T, Ishizaki Y, Murota S
Department of Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, Japan.
Eur J Neurosci. 1998 Feb;10(2):777-81. doi: 10.1046/j.1460-9568.1998.00073.x.
Caspases play a critical role in the cell death machinery in various cell types. Here we investigated the involvement of caspases in the delayed neuronal death after transient global forebrain ischaemia in the gerbil. Intrahippocampal injection of benzyloxycarbonyl-Asp-CH2-dichlorobenzene (zD), an irreversible inhibitor of caspases, saved hippocampal CA1 neurones from chromatin condensation and DNA fragmentation at post-ischaemia day 4, and these neurones maintained normal morphology at day 8 post-insult. Intrahippocampal injection of interleukin-1beta (IL-1beta) after ischaemic insults did not influence the neuroprotective effect of zD, suggesting that the neuroprotective effect does not depend on the inhibition of mature IL-1beta production. Animals that received zD-injection showed significant improvement in step-through and step-down passive avoidance learning at post-ischaemia days 4 and 5, suggesting that neural functions were preserved in these animals. At post-ischaemia day 4, the cleavage of poly(ADP-ribose)polymerase was observed, and this cleavage was almost completely suppressed in zD-injected hippocampus, suggesting involvement of caspase-3 and caspase-3-like caspase in the delayed neuronal death. Our findings indicate that caspases play important roles in the delayed neuronal death after transient global forebrain ischaemia in the gerbil, and suggest that ischaemia-induced brain damage can be blocked by caspase inhibitors.
半胱天冬酶在多种细胞类型的细胞死亡机制中发挥着关键作用。在此，我们研究了半胱天冬酶在沙鼠短暂性全脑缺血后延迟性神经元死亡中的作用。海马内注射苄氧羰基 - 天冬氨酸 - CH2 - 二氯苯（zD），一种不可逆的半胱天冬酶抑制剂，在缺血后第4天使海马CA1神经元免于染色质浓缩和DNA片段化，并且这些神经元在损伤后第8天保持正常形态。缺血性损伤后海马内注射白细胞介素 - 1β（IL - 1β）并不影响zD的神经保护作用，这表明神经保护作用不依赖于对成熟IL - 1β产生的抑制。接受zD注射的动物在缺血后第4天和第5天的穿梭箱和阶梯式被动回避学习中表现出显著改善，这表明这些动物的神经功能得以保留。在缺血后第4天，观察到聚（ADP - 核糖）聚合酶的裂解，并且在注射zD的海马中这种裂解几乎被完全抑制，这表明半胱天冬酶 - 3和类似半胱天冬酶 - 3的半胱天冬酶参与了延迟性神经元死亡。我们的研究结果表明，半胱天冬酶在沙鼠短暂性全脑缺血后延迟性神经元死亡中起重要作用，并表明缺血诱导的脑损伤可被半胱天冬酶抑制剂阻断。
