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首页> 外文期刊>Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism >Caspase inhibitor z-DEVD-fmk attenuates calpain and necrotic cell death in vitro and after traumatic brain injury.
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Caspase inhibitor z-DEVD-fmk attenuates calpain and necrotic cell death in vitro and after traumatic brain injury.

机译：半胱天冬酶抑制剂z-DEVD-fmk可减轻体外和颅脑损伤后钙蛋白酶和坏死细胞的死亡。

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摘要

In studies designed to evaluate the therapeutic window for treatment of traumatic brain injury, the caspase 3 inhibitor z-DEVD-fmk improved neurologic function and reduced lesion volumes when administered at 1 but not at 4, 8, or 24 hours after injury. Moreover, neither caspase 3 nor PARP, a caspase 3 substrate, were cleaved in injured, untreated cortex from 1 to 72 hours after injury. Few cortical neurons expressed active caspase 3 or were TUNEL positive from 6 to 24 hours after injury, and TUNEL staining was primarily Type I (necrotic). Nissl staining revealed extensive neuronal necrosis in the injured cortex from 6 to 24 hours after impact. Considered together, these data suggested that z-DEVD-fmk may reduce neuronal necrosis, so we used an in vitro model of necrotic cell death induced by maitotoxin to test this further and explore the potential mechanism(s) involved. Z-DEVD-fmk (1 nM-100 microM) significantly attenuated maitotoxin induced neuronal cell death and markedly reduced expression of the 145 kD calpain-mediated alpha-spectrin breakdown product after maitotoxin injury. Neither the 120 kD caspase-mediated alpha-spectrin cleavage product nor cathepsin B were expressed after maitotoxin injury. In a cell free assay, z-DEVD-fmk reduced hydrolysis of casein by purified calpain I. Finally, z-DEVD-fmk reduced expression of the 145 kD calpain-mediated alpha-spectrin cleavage fragment after traumatic brain injury in vivo. These data suggest that neuroprotection by z-DEVD-fmk may, in part, reflect inhibition of calpain-related necrotic cell death.
机译：在旨在评估用于治疗颅脑损伤的治疗窗口的研究中，半胱天冬酶3抑制剂z-DEVD-fmk在损伤后1小时而非4、8或24小时给药时，改善了神经功能并减少了病变体积。此外，从损伤后1至72小时，在未处理的受损皮层中均未切割半胱天冬酶3和PARP（半胱天冬酶3的底物）。受伤后6至24小时，很少有皮质神经元表达活跃的caspase 3或TUNEL阳性，而TUNEL染色主要是I型（坏死）。 Nissl染色显示，撞击后6至24小时，受损皮层中广泛的神经元坏死。综合考虑，这些数据表明z-DEVD-fmk可以减少神经元坏死，因此我们使用了由人毒素诱导的坏死性细胞死亡的体外模型来进一步测试这一点，并探索涉及的潜在机制。 Z-DEVD-fmk（1 nM-100 microM）显着减弱了人毒素诱导的神经元细胞死亡，并显着降低了人毒素损伤后145 kD钙蛋白酶介导的α-血影蛋白分解产物的表达。在人毒素损伤后，既不表达120 kD caspase介导的α-血影蛋白裂解产物，也不表达组织蛋白酶B。在无细胞测定中，z-DEVD-fmk减少了酪蛋白I纯化酪蛋白的水解作用。最后，z-DEVD-fmk降低了体内颅脑损伤后145 kD钙蛋白酶介导的α-血影蛋白裂解片段的表达。这些数据表明，z-DEVD-fmk的神经保护作用可能部分反映了钙蛋白酶相关坏死细胞死亡的抑制作用。

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