Persistent microglia-mediated neuroinflammation contributes to the progressive loss of dopaminergic (DA) neurons in Parkinson’s disease (PD). Recently, NOD-like receptor protein 3 (NLRP3) inflammasome-mediated neuroinflammation is considered to influence the pathogenesis of PD profoundly. Promoting DA neuron survival and/or inhibiting neuroinflammation may offer neuroprotection for PD. In the present study, we found that echinacoside (ECH), a phenylethanoid glycoside derived from Cistanche Deserticola, ameliorated motor deficit induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in a mouse PD model, characterized as decreased mobility distance in open field test and average time in rotarod test, as well as increased turn time and total time in pole test. ECH administration promoted the reduction of tyrosine hydroxylase (TH) expression and the number of TH-positive neurons in the substantia nigra (SN) under MPTP injury as the molecular docking simulation predicted that ECH would interact with TH. Moreover, ECH improved cell viability in MPP⁺-damaged SH-SY5Y cell, a cell line for DA neuron, in vitro. Furthermore, ECH administration alleviated MPTP-triggered microglial activation, thus downregulated the expression and activation of NLRP3 inflammasomes in mice SN, along with the involved proteins including Caspase (CASP)-1 and interleukin-1β (IL-1β). The inhibition of NLRP3/CASP-1/IL-1β neuroinflammatory signaling was further confirmed in murine N9 microglia activated by MPP⁺ insult after ECH treatment in vitro. Furthermore, MCC950, a selective inhibitor for NLRP3 activation, reduced the enhancive expression of NLRP3/CASP-1/IL-1β in MPP⁺-insulted N9, and also facilitated the inhibition of inflammation synergistically mediated by ECH treatment. All the collected data revealed that ECH ameliorated PD mice neuroethology through promoting DA neuron survival and inhibiting the activated microglia-mediated NLRP3/CASP-1/IL-1β inflammatory signaling. These findings highlight the crucial roles of NLRP3 inflammasome involved in PD neuropathology and ECH exertes neuroprotection for PD as double-targeting neuroinflammation and DA neuronal survival.

持续存在的小胶质细胞介导的神经炎症导致帕金森病 (PD) 中多巴胺能 (DA) 神经元的逐渐丧失。最近，NOD 样受体蛋白 3 (NLRP3) 炎症小体介导的神经炎症被认为深刻影响 PD 的发病机制。促进 DA 神经元存活和/或抑制神经炎症可能为 PD 提供神经保护。在本研究中，我们发现松果菊苷 (ECH) 是一种源自肉苁蓉的苯乙醇苷，可改善小鼠 PD 中由 1-methyl-4-phenyl-1,2,3,6-四氢吡啶 (MPTP) 诱导的运动缺陷模型，其特点是野外测试中的移动距离和旋转棒测试的平均时间减少，以及杆测试中的转弯时间和总时间增加。ECH 给药促进了 MPTP 损伤下酪氨酸羟化酶 (TH) 表达的减少和黑质 (SN) 中 TH 阳性神经元的数量，因为分子对接模拟预测 ECH 会与 TH 相互作用。此外，ECH 提高了 MPP 中的细胞活力^{+ -}损伤的 SH-SY5Y 细胞，一种体外DA 神经元细胞系。此外，ECH 给药减轻了 MPTP 触发的小胶质细胞激活，从而下调了小鼠 SN 中 NLRP3 炎性体的表达和激活，以及包括 Caspase (CASP)-1 和白细胞介素-1β (IL-1β) 在内的相关蛋白质。NLRP3/CASP-1/IL-1β 神经炎症信号的抑制在体外ECH 处理后由 MPP ⁺损伤激活的鼠 N9 小胶质细胞中得到进一步证实。此外，MCC950 是 NLRP3 激活的选择性抑制剂，可降低 MPP 中 NLRP3/CASP-1/IL-1β 的增强表达⁺-侮辱 N9，并且还促进了由 ECH 治疗协同介导的炎症的抑制。所有收集的数据表明，ECH 通过促进 DA 神经元存活和抑制激活的小胶质细胞介导的 NLRP3/CASP-1/IL-1β 炎症信号传导来改善 PD 小鼠的神经行为学。这些发现强调了 NLRP3 炎症小体在 PD 神经病理学中的关键作用，并且 ECH 作为双重靶向神经炎症和 DA 神经元存活对 PD 发挥神经保护作用。