Neuroprotective effects of PEP-1-carbonyl reductase 1 against oxidative-stress-induced ischemic neuronal cell damage
Neuroprotective effects of PEP-1-carbonyl reductase 1 against oxidative-stress-induced ischemic neuronal cell damage
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DOI：
10.1016/j.freeradbiomed.2014.01.006
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发表时间：
2014-04-01
影响因子：
7.4
通讯作者：
Choi, Soo Young
中科院分区：
文献类型：
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作者：
Kim, Young Nam;Jung, Hyo Young;Choi, Soo Young
人羰基还原酶1 （CBR1）是nadph依赖性短链脱氢酶/还原酶超家族的一员，已知其通过抗氧化功能在神经元细胞存活中发挥重要作用。氧化应激是包括缺血在内的退行性疾病的主要原因之一。然而，CBR1在缺血性损伤中的作用尚不清楚。蛋白质转导结构域如PEP-1是众所周知的，现在通常用于将治疗性蛋白质输送到细胞中。在这项研究中，我们制备了PEP-1-CBR1蛋白，并检测了它是否能保护氧化应激诱导的神经元细胞损伤。PEP-1-CBR1蛋白被有效地转导到海马神经元HT-22细胞中，并对过氧化氢（H2O2）诱导的神经元细胞死亡具有保护作用。转导的PEP-1-CBR1蛋白显著抑制h2o2诱导的活性氧生成、细胞内大分子的氧化、丝裂原活化蛋白激酶的激活以及细胞凋亡。此外，我们在动物模型中证明了转导的PEP-1-CBR1蛋白可显著保护海马CA1区因缺血性损伤导致的神经元细胞死亡。此外，在动物模型中，PEP-1-CBR1蛋白显著降低了胶质细胞的活化和脂质过氧化。这些结果表明，PEP-1-CBR1蛋白在体外和体内对氧化应激诱导的神经元细胞死亡具有显著的保护作用。因此，我们认为PEP-1-CBR1蛋白可能是一种治疗缺血性损伤以及氧化应激诱导的细胞损伤和死亡的治疗剂。(C) 2014爱思唯尔公司版权所有。
Human carbonyl reductase 1 (CBR1) is a member of the NADPH-dependent short-chain dehydrogenase/reductase superfamily that is known to play an important role in neuronal cell survival via its antioxidant function. Oxidative stress is one of the major causes of degenerative disorders including ischemia. However, the role CBR1 plays with regard to ischemic injury is as yet poorly understood. Protein transduction domains such as PEP-1 are well known and now commonly used to deliver therapeutic proteins into cells. In this study, we prepared PEP-1-CBR1 protein and examined whether it protects against oxidative-stress-induced neuronal cell damage. PEP-1-CBR1 protein was efficiently transduced into hippocampal neuronal HT-22 cells and protected against hydrogen peroxide (H2O2)induced neuronal cell death. Transduced PEP-1-CBR1 protein drastically inhibited H2O2-induced reactive oxygen species production, the oxidation of intracellular macromolecules, and the activation of mitogen-activated protein kinases, as well as cellular apoptosis. Furthermore, we demonstrated that transduced PEP-1-CBR1 protein markedly protected against neuronal cell death in the CA1 region of the hippocampus resulting from ischemic injury in an animal model. In addition, PEP-1-CBR1 protein drastically reduced activation of glial cells and lipid peroxidation in an animal model. These results indicate that PEP-1-CBR1 protein significantly protects against oxidative-stress-induced neuronal cell death in vitro and in vivo. Therefore, we suggest that PEP-1-CBR1 protein may be a therapeutic agent for the treatment of ischemic injuries as well as oxidative-stress-induced cell damage and death. (C) 2014 Elsevier Inc. All rights reserved.