Depression Induced by Chronic Unpredictable Mild Stress Increases Susceptibility to Parkinson’s Disease in Mice via Neuroinflammation Mediated by P2X7 Receptor,ACS Chemical Neuroscience

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Depression Induced by Chronic Unpredictable Mild Stress Increases Susceptibility to Parkinson’s Disease in Mice via Neuroinflammation Mediated by P2X7 Receptor
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2021-03-18 , DOI: 10.1021/acschemneuro.1c00095
Chao Ren _{1,

2,

3} , Ling-Xi Li _{1,

2} , An-Qi Dong ₂ , Yu-Ting Zhang _{1,

2} , Hua Hu ₁ , Cheng-Jie Mao ₁ , Fen Wang _{1,

2} , Chun-Feng Liu _{1,

2,

4,

5}

Affiliation

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.

中文翻译：

慢性不可预测的轻度压力引起的抑郁通过 P2X7 受体介导的神经炎症增加小鼠对帕金森病的易感性

抑郁症与帕金森病 (PD) 之间的关系很复杂，目前仍未完全了解。我们研究了抑郁症是否增加了对 PD 的易感性，以及这是否是由小鼠小胶质细胞嘌呤能配体门控离子通道 7 受体 (P2X7R) 介导的神经炎症引起的。抑郁症是由 14 天的慢性不可预测的轻度应激 (CUMS) 诱发的，PD 是由 1 天的急性注射 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱发的。在 MPTP 给药之前，一些小鼠被给予亮蓝色 G (BBG)，一种 P2X7R 抑制剂。抑郁症和运动功能的变化通过蔗糖偏好、尾部悬挂、开放场和旋转杆测试来评估。P2X7R、caspase-1、NLRP3 炎性体、白细胞介素 (IL)-1β、酪氨酸羟化酶 (TH)、采用免疫荧光、免疫组化、western blotting和ELISA检测实验组间小胶质细胞活化情况。CUMS 诱导的抑郁样行为和 MPTP 诱导小鼠的 PD。CUMS小鼠没有运动功能障碍，但MPTP治疗后黑质运动障碍和TH阳性神经元丢失比单独使用MPTP治疗更严重。随着行为的改变，caspase-1、NLRP3和IL-1β等神经炎症标志物增加，小胶质细胞被激活，P2X7R的表达增加。此外，BBG 部分扭转了上述异常情况。总之，我们认为 CUMS 通过促进小胶质细胞的激活和神经炎症来加重 MPTP-PD 模型中多巴胺能神经元的运动障碍和死亡，这可能是由 P2X7R 介导的。

更新日期：2021-04-08

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