Lu Ranran, Zhou Xu, Zhang Lijie, Hao Mengdie, Yang Xinling
Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Ürümqi, Xinjiang, People's Republic of China.
Xinjiang Key Laboratory of Neurological Disease Research, Ürümqi, Xinjiang, People's Republic of China.
J Inflamm Res. 2024 Sep 10;17:6277-6295. doi: 10.2147/JIR.S478683. eCollection 2024.
Parkinson's disease (PD) is a movement disorder characterized by the progressive loss of dopamine neurons. Microglia-mediated neuroinflammation drives disease progression and becomes a critical factor in neuronal degeneration. Recent studies have found that nuclear factor-erythroid 2-related-2 (Nrf2) expression levels are reduced during aging and neurodegenerative diseases, but its regulatory mechanism on microglia-induced neuroinflammation has not been fully elucidated.
In vivo, we used the intraperitoneal injection of the neurotoxic drug neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish an animal model of PD and, at the same time, administered Nrf2 inhibitors ML385 and dimethyl fumarate to regulate Nrf2 protein levels. In vitro, we used si-RNA to knock out the Nrf2 gene to intervene in BV2 cells and used lipopolysaccharide (LPS) to stimulate and induce the cell model.
The study found that inhibition of Nrf2 expression aggravated the motor defects of PD mice, accompanied by a significant loss of dopaminergic neurons in the substantia nigra and striatum of the brain. In addition, after inhibition of Nrf2, the malondialdehyde (MDA) level in the substantia nigra of the midbrain of mice increased, and the levels of superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) decreased, accompanied by the proliferation of microglia and astrocytes. In addition, the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, the assembly of apoptosis-associated speck-like protein containing a CARD (ASC) protein in microglia, and the release of downstream inflammatory factors caspase-1 and interleukin (IL)-1β, were aggravated. At the cellular level, it was found that knocking out the expression of Nrf2 would aggravate the activation of NLRP3 inflammasomes and the assembly of ASC in LPS-induced BV2 cells.
Inhibited Nrf2 activity can reduce the downstream antioxidant enzyme HO-1 and antioxidant levels, induce NLRP3 inflammasome activation and ASC protein assembly in microglia, and ultimately aggravate PD inflammatory response and dopamine neuron degeneration.
帕金森病（PD）是一种以多巴胺能神经元进行性丧失为特征的运动障碍性疾病。小胶质细胞介导的神经炎症推动疾病进展，成为神经元变性的关键因素。最近的研究发现，核因子红细胞2相关因子2（Nrf2）的表达水平在衰老和神经退行性疾病过程中降低，但其对小胶质细胞诱导的神经炎症的调节机制尚未完全阐明。
在体内，我们通过腹腔注射神经毒性药物1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）建立PD动物模型，同时给予Nrf2抑制剂ML385和富马酸二甲酯来调节Nrf2蛋白水平。在体外，我们使用小干扰RNA（si-RNA）敲除Nrf2基因来干预BV2细胞，并使用脂多糖（LPS）刺激诱导细胞模型。
研究发现，抑制Nrf2表达会加重PD小鼠的运动缺陷，同时伴有脑黑质和纹状体中多巴胺能神经元的显著丧失。此外，抑制Nrf2后，小鼠中脑黑质中的丙二醛（MDA）水平升高，超氧化物歧化酶（SOD）和血红素加氧酶-1（HO-1）水平降低，同时伴有小胶质细胞和星形胶质细胞的增殖。此外，含核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎性小体的激活、小胶质细胞中含半胱天冬酶激活和招募结构域的凋亡相关斑点样蛋白（ASC）的组装以及下游炎性因子半胱天冬酶-1和白细胞介素（IL）-1β的释放均加重。在细胞水平上，发现敲除Nrf2的表达会加重LPS诱导的BV2细胞中NLRP3炎性小体的激活和ASC的组装。
Nrf2活性受抑制会降低下游抗氧化酶HO-1和抗氧化水平，诱导小胶质细胞中NLRP3炎性小体激活和ASC蛋白组装，最终加重PD炎症反应和多巴胺能神经元变性。
