Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China.
ACS Chem Neurosci. 2021 Apr 7;12(7):1262-1272. doi: 10.1021/acschemneuro.1c00095. Epub 2021 Mar 18.
The relationship between depression and Parkinson's disease (PD) is complicated and still not fully understood. We investigated whether depression increased the susceptibility to PD and whether this resulted from neuroinflammation mediated by purinergic ligand-gated ion channel 7 receptor (P2X7R) of microglia in mice. Depression was induced by a 14-day chronic unpredictable mild stress (CUMS), and PD was induced by 1-day acute injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Before MPTP administration, some mice were given brilliant blue G (BBG), a P2X7R inhibitor. Changes in depression and motor function were assessed by sucrose preference, tail suspension, open field, and rotating rod tests. Differences in P2X7R, caspase-1, NLRP3 inflammasome, interleukin (IL)-1β, tyrosine hydroxylase (TH), and microglial activation among experimental groups were detected by immunofluorescence, immunohistochemistry, western blotting, and ELISA. CUMS-induced depression-like behavior, and MPTP induced PD in mice. CUMS mice had no motor dysfunction, but the dyskinesia and loss of TH-positive neurons in the substantia nigra after MPTP treatment were more serious than with MPTP treatment alone. With behavioral changes, neuroinflammatory markers, such as caspase-1, NLRP3 and IL-1β increased, and microglia were activated as well as expression of P2X7R increased. Additionally, BBG partly reversed the above abnormalities. Summarily, we suggest that CUMS aggravates dyskinesia and death of dopaminergic neurons in an MPTP-PD model via promoting activation of microglia and neuroinflammation, which may be mediated by P2X7R. Inhibition of P2X7R could be a new control strategy for PD associated with depression.
抑郁与帕金森病（PD）之间的关系复杂，尚未完全阐明。我们研究了抑郁是否会增加 PD 的易感性，以及这种情况是否是由小胶质细胞嘌呤能配体门控离子通道 7 型受体（P2X7R）介导的神经炎症引起的。抑郁通过 14 天慢性不可预测轻度应激（CUMS）诱导，PD 通过 1 天急性注射 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导。在 MPTP 给药前，一些小鼠给予亮蓝 G（BBG），一种 P2X7R 抑制剂。通过蔗糖偏好、悬尾、旷场和旋转棒试验评估抑郁和运动功能的变化。通过免疫荧光、免疫组织化学、western blot 和 ELISA 检测实验组中 P2X7R、半胱氨酸蛋白酶-1（caspase-1）、NLRP3 炎性小体、白细胞介素（IL）-1β、酪氨酸羟化酶（TH）和小胶质细胞激活的差异。CUMS 诱导的抑郁样行为和 MPTP 诱导的小鼠 PD。CUMS 小鼠没有运动功能障碍，但 MPTP 处理后纹状体黑质中多巴胺能神经元的异动和丢失比单独 MPTP 处理更严重。随着行为的变化，神经炎症标志物如 caspase-1、NLRP3 和 IL-1β 增加，小胶质细胞被激活，P2X7R 的表达也增加。此外，BBG 部分逆转了上述异常。总之，我们认为 CUMS 通过促进小胶质细胞激活和神经炎症加重 MPTP-PD 模型中的异动和多巴胺能神经元死亡，这可能是通过 P2X7R 介导的。抑制 P2X7R 可能是一种治疗与抑郁相关的 PD 的新控制策略。
