Bu Lu-Lu, Liu Yi-Qi, Shen Yan, Fan Yun, Yu Wen-Bo, Jiang Dong-Lang, Tang Yi-Lin, Yang Yu-Jie, Wu Ping, Zuo Chuan-Tao, Koprich James B, Liu Feng-Tao, Wu Jian-Jun, Wang Jian
Department of Neurology & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China.
PET Center, Huashan Hospital, Fudan University, Shanghai, 200235, China.
Neurotherapeutics. 2021 Apr;18(2):962-978. doi: 10.1007/s13311-021-01018-5. Epub 2021 Mar 15.
Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 μg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson's disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson's disease.
胰高血糖素样肽-1（GLP-1）受体激动可改善实验动物和患者的帕金森病运动及非运动功能障碍；然而，GLP-1受体激活的疾病修饰机制尚不清楚。本研究调查了艾塞那肽-4（一种GLP-1类似物）是否能挽救运动功能障碍，并在α-突触核蛋白病的帕金森病大鼠模型中发挥疾病修饰作用。该模型通过将腺相关病毒9型（AAV-9）-A53T-α-突触核蛋白单侧注射到右侧黑质致密部建立，然后在注射AAV-9-A53T-α-突触核蛋白2周后，每天腹腔注射两次艾塞那肽-4（5μg/kg/天），持续4周或8周。正电子发射断层扫描/计算机断层扫描（PET/CT）扫描和免疫染色证实，艾塞那肽-4治疗可减轻酪氨酸羟化酶阳性神经元丢失和终末去神经支配，并减轻注射AAV-9-A53T-α-突触核蛋白大鼠黑质纹状体多巴胺能系统中囊泡单胺转运体2表达的降低。它还减轻了行为测试中评估的帕金森病运动功能障碍。此外，通过帕金森病的体内和体外模型，我们表明艾塞那肽-4促进自噬并介导病理性α-突触核蛋白的降解，自噬抑制剂3-甲基腺嘌呤或氯喹可抵消其作用。此外，艾塞那肽-4减轻了注射AAV-9-A53T-α-突触核蛋白大鼠中PI3K/Akt/mTOR通路的失调。综上所述，我们的结果表明，艾塞那肽-4治疗可缓解α-突触核蛋白病帕金森病大鼠模型中的行为缺陷、多巴胺能变性和病理性α-突触核蛋白聚集，并且这些作用是通过抑制PI3K/Akt/mTOR通路增强自噬介导的。鉴于艾塞那肽-4给药的安全性和耐受性，我们的结果表明艾塞那肽-4可能是一种有前途的帕金森病疾病修饰治疗方法。
