Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Oxid Med Cell Longev. 2022 Apr 12;2022:7511393. doi: 10.1155/2022/7511393. eCollection 2022.
Parkinson's disease (PD) is a common neurodegenerative disease characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Our previous study has shown that dexmedetomidine (Dex) can protect mitochondrial function and reduce apoptosis in MPP-induced SH-SY5Y cells. Evidences have shown that mitophagy is related to the development of PD. In this study, we investigated whether Dex can enhance mitophagy in MPTP-induced mice to play a neuroprotective effect. In our experiment, mice were injected with MPTP 30 mg/kg intraperitoneally for 5 consecutive days to establish a PD subacute model. Dex (30, 50, and 100 g/kg) was injected intraperitoneally 30 minutes before each injection of MPTP, respectively. Our results showed that Dex (50 g/kg) most significantly attenuated MPTP-induced motor dysfunction and restored TH-positive neurons in the SN, increased the expression of the antiapoptotic protein Bcl-2, and decreased the expression of apoptotic proteins cleaved casepase3, cleaved casepase9, and Bax. Moreover, Dex increased the activity of mitochondrial Complexes I-IV and decreased the level of oxidative stress, manifesting as decreased MDA levels and increased SOD and GSH-PX levels. Besides, under transmission electron microscopy, Dex increased the mitophagosome which is an autophagosome with a mitochondrion-like structure inside under the electron microscope. In addition, Dex could also increase the expression of mitophagy-related proteins p-AMPK, LC3II/I, PINK1, and Parkin and decrease P62. However, after using Compound C (CC, 10 mg/kg, AMPK inhibitor), the effects of Dex on increasing PINK1/Parkin-induced mitophagy and neuroprotection were attenuated. In conclusion, Dex may improve mitochondrial function by activating AMPK to enhance PINK1/Parkin-induced mitophagy, thereby protecting dopaminergic neurons.
帕金森病（PD）是一种常见的神经退行性疾病，其特征是黑质（SN）中的多巴胺能（DA）神经元退化。我们之前的研究表明，右美托咪定（Dex）可以保护线粒体功能并减少 MPP 诱导的 SH-SY5Y 细胞凋亡。有证据表明，自噬与 PD 的发展有关。在这项研究中，我们研究了 Dex 是否可以增强 MPTP 诱导的小鼠中的自噬作用以发挥神经保护作用。在我们的实验中，小鼠腹腔内注射 MPTP30mg/kg，连续 5 天建立 PD 亚急性模型。Dex（30、50 和 100μg/kg）分别在每次注射 MPTP 前 30 分钟腹腔内注射。结果表明，Dex（50μg/kg）最显著地减轻了 MPTP 诱导的运动功能障碍并恢复了 SN 中的 TH 阳性神经元，增加了抗凋亡蛋白 Bcl-2 的表达，减少了凋亡蛋白 cleaved casepase3、cleaved casepase9 和 Bax 的表达。此外，Dex 增加了线粒体复合物 I-IV 的活性并降低了氧化应激水平，表现为 MDA 水平降低，SOD 和 GSH-PX 水平升高。此外，在透射电子显微镜下，Dex 增加了噬线粒体体的数量，即在电子显微镜下具有线粒体样结构的自噬体。此外，Dex 还可以增加自噬相关蛋白 p-AMPK、LC3II/I、PINK1 和 Parkin 的表达，并降低 P62 的表达。然而，在用 Compound C（CC，10mg/kg，AMPK 抑制剂）处理后，Dex 增加 PINK1/Parkin 诱导的自噬和神经保护作用的效果减弱。总之，Dex 可能通过激活 AMPK 来改善线粒体功能，从而增强 PINK1/Parkin 诱导的自噬，从而保护多巴胺能神经元。
