Inflammation is one of the pathogenic processes in Parkinson’s disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg⁻¹·d⁻¹, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1β in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1β, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100–400 μM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 μM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.

炎症是帕金森病 (PD) 的致病过程之一。多巴胺受体激动剂普拉克索 (PPX) 在临床上广泛用于 PD 治疗。许多研究表明，PPX 对多巴胺能 (DA) 神经元具有神经保护作用，但 PPX 对 DA 神经元保护作用的分子机制尚未完全阐明。在本研究中，我们研究了 PPX 是否调节 PD 相关的神经炎症和潜在机制。通过双侧纹状体注射脂多糖（LPS）在小鼠中建立PD模型。给小鼠施用 PPX（0.5 mg·kg ^-1 ·d ^-1, ip) LPS 注射前 3 天，以及手术后 3 天或 21 天，分别用于生化和组织学分析。我们表明，PPX 给药显着减轻了 DA 神经元的损失，并抑制了 LPS 注射小鼠黑质中星形胶质细胞的活化和促炎细胞因子 IL-1β 的水平。此外，PPX 给药显着降低了 NLRP3 炎性体相关蛋白的表达，即纹状体中 caspase-1、IL-1β 的裂解形式和含有 caspase 募集结构域 (ASC) 的凋亡相关斑点样蛋白。这些结果在体外 LPS+ATP 刺激的原代小鼠星形胶质细胞中得到验证。值得注意的是，我们发现 PPX (100–400 μM) 剂量依赖性地增强了星形胶质细胞中的自噬活性，这通过 LC3-II 和 BECN1 蛋白表达的升高以及 GFP-LC3 斑点形成的增加得到证明。PPX 对星形胶质细胞 NLRP3 炎性体和自噬的相反作用被消除了Drd3 耗尽。此外，我们证明了在体外用自噬抑制剂氯喹 (40 μM) 预处理星形胶质细胞和在体内敲除星形胶质细胞特异性Atg5 都可以阻断 PPX 引起的对 NLRP3 炎性体的抑制和对 DA 神经元损伤的保护。总而言之，这项研究通过 Drd3 依赖性增强星形胶质细胞自噬活性证明了 PPX 的抗神经炎症活性，并揭示了 PPX 在 PD 治疗中产生有益作用的新机制。