Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity
Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity
复制标题
肌肽通过减少谷氨酸兴奋性毒性来预防组氨酸脱羧酶敲除小鼠的永久性脑缺血
DOI：
10.1016/j.freeradbiomed.2009.12.021
复制
发表时间：
2010-03-01
影响因子：
7.4
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Shen, Yao;He, Ping;Chen, Zhong
最近，我们发现肌肽通过组胺能途径对NMDA诱导的PC12细胞的兴奋性毒性具有保护作用。然而，肌肽代谢通路是否也在缺血脑中发挥保护作用尚不清楚。利用永久性大脑中动脉闭塞(PMCAO)小鼠模型，我们发现在组氨酸脱羧酶基因敲除小鼠和相应的野生型小鼠中，肌肽均能显著改善神经功能和缩小脑梗塞范围。肌肽可降低缺血星形胶质细胞谷氨酸水平，保护谷氨酸转运体-1(GLT-1)的表达，但不影响谷氨酸/天冬氨酸转运体的表达。抑制缺氧缺糖诱导的星形胶质细胞DeltaPsi(M)的消散和线粒体活性氧(ROS)的产生。此外，肌肽还降低了线粒体ROS，并逆转了鱼藤酮引起的GLT-1的降低。这些发现首次证明肌肽在pMCAO中的作用机制可能不是通过组胺能途径，而是通过改善线粒体功能而有效地调节星形胶质细胞中GLT-1的表达来减轻谷氨酸的兴奋性毒性。因此，我们的研究揭示了一种新的抗兴奋性毒性药物治疗缺血性损伤。(C)2009 Elsevier Inc.保留所有权利。
Recently, we showed that carnosine protects against NMDA-induced excitotoxicity in differentiated PC12 cells through a histaminergic pathway. However, whether the protective effect of the carnosine metabolic pathway also occurs in ischemic brain is unknown. Utilizing the model of permanent middle cerebral artery occlusion (pMCAO) in mice, we found that carnosine significantly improved neurological function and decreased infarct size in both histidine decarboxylase knockout and the corresponding wild-type mice to the same extent. Carnosine decreased the glutamate levels and preserved the expression of glutamate transporter-1 (GLT-1) but not the glutamate/aspartate transporter in astrocytes exposed to ischemia in vivo and in vitro. It suppressed the dissipation of Delta Psi(m) and generation of mitochondrial reactive oxygen species (ROS) induced by oxygen-glucose deprivation in astrocytes. Furthermore, carnosine also decreased the mitochondrial ROS and reversed the decrease in GLT-1 induced by rotenone. These findings are the first to demonstrate that the mechanism of carnosine action in pMCAO may not be mediated by the histaminergic pathway, but by reducing glutamate excitotoxicity through the effective regulation of the expression of GLT-1 in astrocytes due to improved mitochondrial function. Thus, our study reveals a novel antiexcitotoxic agent in ischemic injury. (C) 2009 Elsevier Inc. All rights reserved.