Gu Qin, Zhai Lijing, Feng Xing, Chen Jing, Miao Zhigang, Ren Liyan, Qian Xuanchen, Yu Jian, Li Yan, Xu Xingshun, Liu Chun-Feng
Department of Neurology, The Affiliated Children Hospital of Soochow University, Suzhou, Jiangsu, China; Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Neurochem Int. 2013 Nov;63(6):535-40. doi: 10.1016/j.neuint.2013.09.017. Epub 2013 Sep 29.
Apelin is an endogenous ligand of G protein-coupled receptor-apelin and angiotensin-1-like receptor (APJ). The biological effects of apelin-APJ system are reported in multiple systems including cardiovascular, endocrinal, and gastrointestinal system. Previous studies had shown that apelin-13 is a potential protective agent on cardiac ischemia; however, the role of apelin in the central nervous system remained unknown. In this study, we investigated therapeutic effects of apelin-36, a long form of apelin, in ischemic brain injury models. We found that apelin-36 reduced cerebral infarct volume in the middle cerebral artery occlusion (MCAO) model and the neonatal hypoxic/ischemic (H/I) injury model. Apelin-36 improved neurological deficits in the MCAO model and promoted long-term functional recovery after H/I brain injury. We further explored the protective mechanisms of apelin-36 on H/I brain injury. We clearly demonstrated that apelin-36 significantly reduced the levels of cleaved caspase-3 and Bax, two well-established apoptotic markers after H/I injury, indicating the anti-apoptotic activity of apelin-36 in ischemic injury. Since apelin-36 increased the level of phosphorylated Akt after H/I injury, we treated neonates with a specific PI3K inhibitor LY294002. We found that LY294002 decreased the phosphorylated Akt level and attenuated protective effects of apelin-36 on apoptosis. These suggested that the PI3K/Akt pathway was at least in part involved in the anti-apoptotic mechanisms of apelin-36. Our findings demonstrated that apelin-36 was a promising therapeutic agent on the treatment of ischemic brain injury.
阿片肽是G蛋白偶联受体阿片肽和血管紧张素1样受体（APJ）的内源性配体。阿片肽-APJ系统的生物学效应在包括心血管、内分泌和胃肠道系统在内的多个系统中均有报道。先前的研究表明，阿片肽-13是心脏缺血的潜在保护剂；然而，阿片肽在中枢神经系统中的作用仍不清楚。在本研究中，我们研究了阿片肽的一种长形式——阿片肽-36在缺血性脑损伤模型中的治疗作用。我们发现，阿片肽-36在大脑中动脉闭塞（MCAO）模型和新生儿缺氧缺血（H/I）损伤模型中可减少脑梗死体积。阿片肽-36改善了MCAO模型中的神经功能缺损，并促进了H/I脑损伤后的长期功能恢复。我们进一步探讨了阿片肽-36对H/I脑损伤的保护机制。我们清楚地证明，阿片肽-36显著降低了H/I损伤后两种公认的凋亡标志物——裂解的半胱天冬酶-3和Bax的水平，表明阿片肽-36在缺血性损伤中具有抗凋亡活性。由于阿片肽-36在H/I损伤后增加了磷酸化Akt的水平，我们用特异性PI3K抑制剂LY294002处理新生动物。我们发现，LY294002降低了磷酸化Akt水平，并减弱了阿片肽-36对凋亡的保护作用。这些结果表明，PI3K/Akt通路至少部分参与了阿片肽-36的抗凋亡机制。我们的研究结果表明，阿片肽-36是治疗缺血性脑损伤的一种有前景的治疗药物。
