Translational Research Center, Inha University Hospital, Incheon, Republic of Korea.
Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea.
Cell Death Dis. 2024 Nov 22;15(11):854. doi: 10.1038/s41419-024-07252-x.
Levodopa (L-DOPA) treatment is a clinically effective strategy for improving motor function in patients with ischemic stroke. However, the mechanisms by which modulating the dopamine system relieves the pathology of the ischemic brain remain unclear. Emerging evidence from an experimental mouse model of ischemic stroke, established by middle cerebral artery occlusion (MCAO), suggested that L-DOPA has the potential to modulate the inflammatory and immune response that occurs during a stroke. Here, we aimed to demonstrate the therapeutic effect of L-DOPA in regulating the systemic immune response and improving functional deficits in mice with ischemia. Transient MCAO led to progressive degeneration of nigrostriatal dopamine neurons and significant rotational behavior in mice. Exogenous L-DOPA treatment attenuated the striatonigral degeneration and reversed motor behavioral impairment. Notably, treatment with L-DOPA significantly increased IL-13 but reduced IFN-γ in infarct lesions. To investigate the role of IL-13 in motor behavior, we stereotaxically injected anti-IL-13 antibodies into the infarct area of the mouse brain one week after MCAO, followed by L-DOPA treatment. The intervention reduced dopamine, IL-13, and IL-10 levels and exacerbated motor function. IL-13 is potentially expressed on CD4 T cells, while IL-10 is mainly expressed on microglia rather than astrocytes. Finally, IL-13 activates the phagocytosis of microglia, which may contribute to neuroprotection by eliminating degenerating neurons. Our study provides evidence that the L-DOPA-activated dopamine system modulates peripheral immune cells, resulting in the expression of anti-inflammatory and neuroprotective cytokines in mice with ischemic stroke.
左旋多巴（L-DOPA）治疗是改善缺血性中风患者运动功能的一种临床有效策略。然而，调节多巴胺系统缓解缺血性大脑病理的机制仍不清楚。通过大脑中动脉闭塞（MCAO）建立的缺血性中风实验小鼠模型的新证据表明，L-DOPA 有可能调节中风期间发生的炎症和免疫反应。在这里，我们旨在证明 L-DOPA 在调节系统性免疫反应和改善缺血小鼠的功能缺陷方面的治疗效果。短暂性 MCAO 导致黑质纹状体多巴胺神经元进行性退化和小鼠出现明显的旋转行为。外源性 L-DOPA 治疗减轻纹状体黑质变性并逆转运动行为障碍。值得注意的是，L-DOPA 治疗显着增加了梗死病变中的 IL-13，但减少了 IFN-γ。为了研究 IL-13 在运动行为中的作用，我们在 MCAO 后一周将抗 IL-13 抗体立体定向注射到小鼠脑梗死区，然后进行 L-DOPA 治疗。该干预措施降低了多巴胺、IL-13 和 IL-10 水平，并加重了运动功能障碍。IL-13 可能在 CD4 T 细胞上表达，而 IL-10 主要在小胶质细胞上表达，而不是星形胶质细胞上表达。最后，IL-13 激活小胶质细胞的吞噬作用，这可能通过消除变性神经元来发挥神经保护作用。我们的研究提供了证据表明，L-DOPA 激活的多巴胺系统调节外周免疫细胞，导致缺血性中风小鼠表达抗炎和神经保护细胞因子。
