Inhibition of interleukin 1 beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage
Inhibition of interleukin 1 beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage
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DOI：
10.1073/pnas.94.5.2007
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发表时间：
1997-03-04
影响因子：
11.1
通讯作者：
Moskowitz, MA
中科院分区：
文献类型：
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作者：
Hara, H;Friedlander, RM;Moskowitz, MA
白介素 1 β 转换酶 (ICE) 家族在程序性细胞死亡中发挥着关键作用，并与中风和神经退行性疾病有关。在丝状大脑中动脉闭塞后的再灌注过程中，缺血性小鼠大脑中 ICE 样裂解产物和组织免疫反应性白细胞介素 1 β (IL-1 β) 水平增加，缺血性损伤减少 脑室内注射 ICE 样蛋白酶抑制剂、N-苄氧羰基-Val-Ala-Asp-氟甲基酮 (z-VAD.FMK)、乙酰基-Tyr-Val-Ala-Asp-氯甲基酮或 CPP32 样半胱天冬酶的相对选择性抑制剂， N-苄氧基羰基-Asp-Glu-Val-Asp-氟甲基酮，但不是组织蛋白酶 B 抑制剂，N-苄氧基羰基-Phe-Ala-氟甲基酮。 z-VAD.FMK 降低了缺血小鼠大脑中的 ICE 样裂解产物和组织免疫反应性 IL-1 β 水平，并且当给予大鼠时也减少了组织损伤。只有 z-VAD.FMK 和乙酰基-Tyr r-Val-Ala-Asp-氯甲基酮减少了脑肿胀，而 N-苄氧基羰基-Asp-Glu-Val-Asp-氟甲基酮没有减弱缺血引起的组织 IL-1 β 水平的增加。三种半胱氨酸蛋白酶抑制剂显着改善了行为缺陷， 从而表明缺血神经元组织的功能恢复可以在与细胞凋亡相关的酶的阻断后进行。最后，我们检查了 z-VAD、FiMK 对兴奋性毒性的影响，发现它可以防止 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯诱导或在较小程度上 N-甲基-D-天冬氨酸诱导。 因此，ICE 样和 CPP32 样半胱天冬酶有助于缺血性和兴奋性脑损伤中的细胞死亡机制，并为中风和神经退行性脑损伤提供治疗靶点。
The interleukin 1 beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases, During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1 beta (IL-1 beta) levels increased in ischemic mouse brain, Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1 beta levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr r-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1 beta levels, The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death, Finally, we examined the effect of z-VAD,FiMK on excitotoxicity and found that it protected against alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain damage, Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.