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中华诊断学电子杂志 ›› 2023, Vol. 11 ›› Issue (04) : 276 -282. doi: 10.3877/cma.j.issn.2095-655X.2023.04.012

综述

Apelin/APJ系统对帕金森病模型的神经保护作用及机制研究进展
郭如烨, 孟黎明, 陈楠, 宋玉莹, 尹海燕, 郭岩()   
  1. 272013 济宁医学院临床医学院
    272067 济宁医学院基础医学院
  • 收稿日期:2022-09-02 出版日期:2023-11-26
  • 通信作者: 郭岩
  • 基金资助:
    国家自然科学基金(82000979); 济宁医学院教师科研扶持基金(JYFC2019KJ001); 济宁医学院大学生创新创业训练计划项目(cx2020008)

Research status on the neuroprotective efficacy and mechanism of Apelin/APJ system in Parkinson disease model

Ruye Guo, Liming Meng, Nan Chen, Yuying Song, Haiyan Yin, Yan Guo()   

  1. College of Clinical Medicine, Jining Medical University, Jining 272013, China
    Department of Basic Medicine, Jining Medical University, Jining 272067, China
  • Received:2022-09-02 Published:2023-11-26
  • Corresponding author: Yan Guo
引用本文:

郭如烨, 孟黎明, 陈楠, 宋玉莹, 尹海燕, 郭岩. Apelin/APJ系统对帕金森病模型的神经保护作用及机制研究进展[J/OL]. 中华诊断学电子杂志, 2023, 11(04): 276-282.

Ruye Guo, Liming Meng, Nan Chen, Yuying Song, Haiyan Yin, Yan Guo. Research status on the neuroprotective efficacy and mechanism of Apelin/APJ system in Parkinson disease model[J/OL]. Chinese Journal of Diagnostics(Electronic Edition), 2023, 11(04): 276-282.

目前,帕金森病(PD)的发病机制仍不明确,也尚未有针对PD缓解的有效策略。越来越多的研究表明,自噬失调、线粒体损伤、内质网应激、氧化应激和过度神经炎症之间的复杂相互作用是PD发病机制的基础。Apelin是一种内源性神经肽,作为孤儿G蛋白偶联受体APJ的配体,可能通过抑制细胞凋亡和多巴胺能神经元丢失,增强自噬和抗氧化,抑制内质网应激及抑制过度神经炎症,起到神经保护作用,主要涉及PI3K/Akt/mTOR、ERK1/2和IRE1α/XBP1/CHOP等信号通路。笔者主要对Apelin/APJ轴在PD中的神经保护作用及机制研究进行综述。

The pathogenesis of Parkinson′s disease (PD) is still unknown. There is still no effective disease-modifying strategy for PD, which is mostly managed symptomatically. A growing amount of preclinical evidence suggests the pathogenesis of PD is driven by a complex interaction of autophagy dysregulation, mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, and excessive neuroinflammation. Emerging preclinical evidence suggests that Apelin, an endogenous neuropeptide that acts as a ligand of the orphan G protein-coupled receptor APJ, may play an important neuroprotective role in the pathogenesis of PD by inhibiting apoptosis and dopaminergic neuronal loss, enhancing autophagy and antioxidant effects suppressing, endoplasmic reticulum stress, and preventing excessive neuroinflammation, which mainly involves. PI3K/Akt/mTOR, ERK1/2, and IRE1/XBP1/CHOP and other signaling pathways involved. Given the growing preclinical evidence on the role of the Apelin/APJ axis in PD pathogenesis and the lack of a comprehensive review, we discuss the emerging role of the Apelin/APJ axis in PD pathophysiology and its great potential as a future therapeutic target in this article.

图1 Apelin/APJ通过Gαi信号传导通路在PD发病机制中的作用注:Apelin与其G蛋白偶联受体APJ结合,通过Gαi,导致PI3K/Akt和PKC/ERK 1/2通路的激活,参与细胞凋亡、神经炎症和氧化应激的调节。PI3K为磷酸肌醇-3-激酶;Akt为蛋白激酶B;mTOR为哺乳动物雷帕霉素靶蛋白;PKC为蛋白激酶C;MEK为促分裂原活化蛋白激酶;ERK 1/2为细胞外信号调节激酶
图2 Apelin/APJ信号通过Gαq信号转导通路在PD发病机制中的作用注:Apelin与其G蛋白偶联受体APJ结合,通过Gαq,激活AMPK/mTOR/ULK1信号通路增强自噬;激活AMPK/GSK-3β/Nrf2通路发挥抗氧化作用;通过调节AMPK/TXNIP/NLRP3信号通路抑制神经炎症;通过下调IRE1α/XBP1/CHOP信号通路抑制内质网应激。AMPK为腺苷酸活化蛋白激酶;GSK-3β为糖原合成酶激酶3β;Nrf2为核转录因子红系2相关因子2;TXNIP为硫氧还蛋白互作蛋白;NLRP3为NOD样受体热蛋白结构域相关蛋白3;IRE 1α为肌醇酶1α;XBP1 X为盒结合蛋白1;CHOP为C/EBP同源蛋白;mTOR为哺乳动物雷帕霉素靶蛋白;ULK1为动物自噬启动蛋白
表1 在不同的帕金森病模型中部分Apelin亚型的神经保护作用
序号 Apelin亚型 PD模型 相关通路及作用 参考文献
1 Apelin-13 体外模型(6-OHDA处理的SH-SY5Y细胞) 1.与APJ相互作用以激活PI3K信号传导,抑制神经毒性和细胞凋亡
2.抑制caspase-3激活、细胞色素c释放,保持线粒体膜电位
3.减少ROS产生
14
2 Apelin-13 体外模型(鱼藤酮处理的SH-SY5Y细胞) 1.通过上调AMPK/mTOR/ULK1信号通路激活自噬以发挥神经保护作用
2.增加LC3B-Ⅱ/LC3B-Ⅰ比例、降低p62和α-突触核蛋白水平
12
3 Apelin-13 体内模型(MPTP处理的小鼠) 1.增强与LC3B-Ⅱ增加相关的自噬并减少p62
2.通过抑制ERS保护多巴胺能神经元细胞(减少GRP78,下调SNpc中的IRE 1α/XBP1/CHOP信号通路)
43
4 Apelin-36 体外模型(MPP+处理的SH-SY5Y细胞) 1.通过调节PI3K/Akt/mTOR信号通路抑制细胞凋亡
2.通过增加LC3B-Ⅱ/LC3B-Ⅰ比例诱导自噬,通过PI3K/Akt/mTOR轴降低p62表达
3.降低α-突触核蛋白表达
4.通过抑制ERS增加酪氨酸羟化酶表达介导的细胞凋亡
5.减轻ERS诱导的神经元损失,抑制ERS,减少GRP78、CHOP、裂解的caspase-12
20
5 Apelin-36 体内外模型 1.抑制SNpc中的ERS,减少CHOP、GRP78、多巴胺能神经元中裂解的caspase-12
2.调节氧化应激,自噬和细胞凋亡
44
6 Apelin-36 体内模型(MPTP处理的小鼠) 1.抑制ASK1/JNK/caspase-3凋亡通路
2.促进自噬,增加LC3B-Ⅱ/LC3B-Ⅰ比例,降低p62
3.改善包括SOD和GSH在内的抗氧化细胞机制
4.降低丙二醛的含量
5.降低小鼠SNpc和STR中的诱生型一氧化氮合酶蛋白和mRNA表达
21
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