Endogenous calcitonin gene-related peptide suppresses ischemic brain injuries and progression of cognitive decline
Endogenous calcitonin gene-related peptide suppresses ischemic brain injuries and progression of cognitive decline
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DOI：
10.1097/hjh.0000000000001649
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发表时间：
2017-12
影响因子：
4.9
通讯作者：
Liuyu Zhai;T. Sakurai;Akiko Kamiyoshi;Yuka Ichikawa-Shindo;Hisaka Kawate;Megumu Tanaka;Xian Xian-Xian;Kazutaka Hirabayashi;Kun Dai;Nanqi Cui;Keiya Tanimura;Teng Liu;Yangxuan Wei;Masaaki Tanaka;H. Tomiyama;Akihiro Yamauchi;Kyoko Igarashi;T. Shindo
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文献类型：
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作者：
Liuyu Zhai;T. Sakurai;Akiko Kamiyoshi;Yuka Ichikawa-Shindo;Hisaka Kawate;Megumu Tanaka;Xian Xian-Xian;Kazutaka Hirabayashi;Kun Dai;Nanqi Cui;Keiya Tanimura;Teng Liu;Yangxuan Wei;Masaaki Tanaka;H. Tomiyama;Akihiro Yamauchi;Kyoko Igarashi;T. Shindo
背景资料：降钙素基因相关肽（CGRP）是由降钙素/CGRP基因的转录物的选择性剪接产生的37个氨基酸的肽。CGRP最初被鉴定为一种强血管扩张和扩张肽，现在已知是一种分布在包括大脑在内的各种器官中的多效性分子。方法：本研究采用CGRP基因敲除小鼠（CGRP-/-），观察内源性CGRP在脑缺血中的作用。采用大脑中动脉闭塞（MCAO）和双侧颈总动脉狭窄（BCAS）模型，建立急性和慢性脑缺血模型。结果：在野生型小鼠大脑皮质，CGRP表达在急性梗死后上调。在CGRP−/−的MCAO或BCAS中，脑血流量的恢复较慢，并表现出更广泛的神经元细胞死亡。在缺血急性期，CGRP-/-中炎症细胞因子的表达高于野生型。慢性期的病理分析显示，CGRP−/−比野生型更广泛的神经元细胞丢失和脱髓鞘以及更高水平的氧化应激。CGRP−/−也显示出较少的代偿性毛细血管生长。在八臂径向迷宫测试中，CGRP−/−表现出比野生型更差的参考记忆。另一方面，CGRP给药促进脑缺血后的脑血流恢复。我们还发现CGRP直接抑制原代皮层神经元的细胞死亡。结论：内源性CGRP对缺血性神经细胞损伤具有保护作用。因此，CGRP可能是用于治疗脑缺血和认知衰退进展的新候选物。
Background: Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide and produced by alternative splicing of the transcript of the calcitonin/CGRP gene. Originally identified as a strong vasodilatory and hypotensive peptide, CGRP is now known to be a pleiotropic molecule distributed in various organs, including the brain. Method: In this study, we used CGRP knockout mice (CGRP−/−) to examine the actions of endogenous CGRP during cerebral ischemia. To induce acute and chronic cerebral ischemia, mice were subjected to middle cerebral artery occlusion (MCAO) and bilateral common carotid artery stenosis (BCAS). Results: In the cerebral cortex of wild-type mice, CGRP expression was upregulated after acute infarction. In CGRP−/− subjected to MCAO or BCAS, recovery of cerebral blood flow was slower and exhibited more extensive neuronal cell death. Expression of the inflammatory cytokines was higher in CGRP−/− than wild type in the acute phase of ischemia. Pathological analysis during the chronic phase revealed more extensive neuronal cell loss and demyelination and higher levels of oxidative stress in CGRP−/− than wild-type. CGRP−/− also showed less compensatory capillary growth. In an eight-arm radial maze test, CGRP−/− exhibited poorer reference memory than wild-type. On the other hand, CGRP administration promoted cerebral blood flow recovery after cerebral ischemia. We also found that CGRP directly inhibited the cell death of primary cortical neurons. Conclusion: These results indicate endogenous CGRP is protective against ischemia-induced neuronal cell injury. CGRP could, thus, be a novel candidate for use in the treatment of both cerebral ischemia and progression of cognitive decline.