Calpain inhibitor MDL 28170 protects hypoxic-ischernic brain injury in neonatal rats by inhibition of both apoptosis and necrosis
Calpain inhibitor MDL 28170 protects hypoxic-ischernic brain injury in neonatal rats by inhibition of both apoptosis and necrosis
复制标题
DOI：
10.1016/j.brainres.2004.12.050
复制
发表时间：
2005-03-10
期刊：
影响因子：
2.9
通讯作者：
Takada, G
中科院分区：
文献类型：
--
作者：
Kawamura, M;Nakajima, W;Takada, G
MDL 28170是一种CNS穿透性钙蛋白酶抑制剂，我们使用Rice-Vannucci模型研究了MDL 28170对未成熟脑缺氧缺血性脑损伤的影响。在低氧暴露后，立即腹膜内注射24 mg/kg MDL 28170作为初始剂量，随后每4小时注射12 mg/kg，HI后12小时内总剂量为60 mg/kg。溶剂对照组改为花生油注射液。脑损伤的宏观评估揭示了HI后12小时MDL 28170的神经保护作用。细胞死亡的神经病理学定量分析表明，MDL 28170显着减少所有检查区域的坏死细胞的数量，除了扣带回皮质，尾壳核，顶叶皮质，海马CA 1区，和laterodoral丘脑的凋亡细胞的数量。Western印迹显示MDL 28170抑制皮质、海马、丘脑和纹状体中α-血影蛋白分解产物（SBDP）的145/150 kDa亚基，以及除纹状体外所有区域中SBDP的120 kDa亚基。这表明MDL 28170分别抑制钙蛋白酶和半胱氨酸蛋白酶-3的活化。我们的结果表明，缺氧后注射MDL 28170通过减少坏死和凋亡对HI新生大鼠脑具有神经保护作用。SBDP表达还表明MDL 28170注射抑制HI损伤后钙蛋白酶和半胱天冬酶-3活化。(c)2005 Elsevier B.V保留所有权利。
MDL 28170 is a CNS-penetrating calpain inhibitor, and we examined the effects of MDL 28170 on hypoxic-ischemic brain injury in immature brain using the Rice-Vannucci model. Immediately after hypoxic exposure, 24 mg/kg of MDL 28170 was injected intraperitoneally as an initial dose, followed by 12 mg/kg every 4 h for a total dose of 60 mg/kg over 12 h post-HI. A vehicle control group received peanut oil injection instead. Macroscopic evaluation of brain injury revealed the neuroprotective effect of MDL 28170 after 12 It post-HI. Neuropathological quantitative analysis of cell death showed that MDL 28170 significantly decreased the number of necrotic cells in all the examined regions except for cingular cortex, and the number of apoptotic cells in caudate putamen, parietal cortex, hippocampus CA1, and laterodorsal thalamus. Western blots showed that MDL 28170 suppressed 145/150 kDa subunits of alpha-spectrin breakdown products (SBDP) in cortex, hippocampus, thalamus, and striatum, and also 120-kDa subunit of SBDP in all regions except for striatum. This suggests that MDL 28170 inhibited activation of calpain and caspase-3, respectively.Our results indicate that post-hypoxic MDL 28170 injection is neuroprotective in HI newborn rat brain by decreasing both necrosis and apoptosis. SBDP expression also suggests that MDL 28170 injection inhibits both calpain and caspase-3 activation after HI insult. (c) 2005 Elsevier B.V All rights reserved.