A NOVEL CALPAIN INHIBITOR, ((1S)-1((((1S)-1-BENZYL-3-CYCLOPROPYLAMINO-2,3-DI-OXOPROPYL)AMINO)CARBONYL)-3-METHYLBUTYL) CARBAMIC ACID 5-METHOXY-3-OXAPENTYL ESTER, PROTECTS NEURONAL CELLS FROM CEREBRAL ISCHEMIA-INDUCED DAMAGE IN MICE
A NOVEL CALPAIN INHIBITOR, ((1S)-1((((1S)-1-BENZYL-3-CYCLOPROPYLAMINO-2,3-DI-OXOPROPYL)AMINO)CARBONYL)-3-METHYLBUTYL) CARBAMIC ACID 5-METHOXY-3-OXAPENTYL ESTER, PROTECTS NEURONAL CELLS FROM CEREBRAL ISCHEMIA-INDUCED DAMAGE IN MICE
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DOI：
10.1016/j.neuroscience.2008.09.007
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发表时间：
2008-11-19
期刊：
影响因子：
3.3
通讯作者：
Hara, H.
中科院分区：
文献类型：
--
作者：
Koumura, A.;Nonaka, Y.;Hara, H.
脑缺血诱导Ca ~（2+）内流进入神经细胞，并激活包括钙蛋白酶在内的多种蛋白酶。由于钙蛋白酶在神经细胞死亡中起重要作用，钙蛋白酶抑制剂可能成为治疗脑梗死的潜在药物。（（1 S）-1-（1 S）-1-苄基-3-环丙基氨基-2，3-二氧丙基）氨基）羰基）-3-甲基丁基）氨基甲酸5-甲氧基-3-氧戊酯（SNJ-1945）是一种新型钙蛋白酶抑制剂，具有良好的膜通透性和水溶性。本实验观察了SNJ-1945对小鼠大脑中动脉闭塞（MCAO）所致局灶性脑缺血的影响。通过评估MCAO后24 h或72 h的神经功能缺损以及检查脑切片的2，3，5-三苯基氯化四氮唑（TTC）染色和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色来评价脑损伤。当在MCAO后1小时注射时，30和100 mg/kg的SNJ-1945，i. p.减少了梗塞体积，并改善了各自在24小时评估的神经功能缺损。100 mg/kg，i. p.的SNJ-1945在72 h时也显示出神经保护作用，并在24 h时减少TUNEL阳性细胞的数量。SNJ-1945能够防止神经元细胞死亡，即使在MCAO后6小时注射，但不能在8小时注射。此外，SNJ-1945在缺血脑半球中在6 h和12 h降低切割的α-血影蛋白，在12 h和24 h降低活性caspase-3。这些发现表明，SNJ-1945抑制钙蛋白酶的激活，并提供神经保护作用，对急性脑缺血的影响，即使给药后6小时MCAO小鼠。因此，SNJ-1945可能是治疗中风的潜在药物。(C)2008年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Cerebral ischemia induces Ca2+ influx into neuronal cells, and activates several proteases including calpains. Since calpains play important roles in neuronal cell death, calpain inhibitors may have potential as drugs for cerebral infarction. ((1S)-1((((1S)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl) carbamic acid 5-methoxy3-oxapentyl ester (SNJ-1945) is a novel calpain inhibitor that has good membrane permeability and water solubility. We evaluated the effect of SNJ-1945 on the focal brain ischemia induced by middle cerebral artery occlusion (MCAO) in mice. Brain damage was evaluated by assessing neurological deficits at 24 h or 72 h after MCAO and also by examining 2,3,5-triphenyltetrazolium chloride (TTC) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining of brain sections. When injected at 1 h after MCAO, SNJ-1945 at 30 and 100 mg/kg, i.p. decreased the infarction volume and improved the neurological deficits each assessed at 24 h. SNJ-1945 at 100 mg/kg, i.p. also showed neuroprotective effects at 72 h and reduced the number of TUNEL-positive cells at 24 h. SNJ-1945 was able to prevent neuronal cell death even when it was injected at up to 6 h, but not at 8 h, after MCAO. In addition, SNJ-1945 decreased cleaved a-spectrin at 6 h and 12 h, and active caspase-3 at 12 h and 24 h in ischemic brain hemisphere. These findings indicate that SNJ-1945 inhibits the activation of calpain, and offers neuroprotection against the effects of acute cerebral ischemia in mice even when given up to 6 h after MCAO. SNJ-1945 may therefore be a potential drug for stroke. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.