Shandong Provincial Medicine and Health Key Laboratory of Clinical Anesthesia, School of Anesthesiology, Weifang Medical University, Weifang 261053, China.
Department of Thoracic Surgery, Weifang People's Hospital, Weifang 261000, China.
Oxid Med Cell Longev. 2022 Mar 30;2022:5896699. doi: 10.1155/2022/5896699. eCollection 2022.
Neuroinflammation is a critical pathological process of neurodegenerative diseases, and alleviating the inflammatory response caused by abnormally activated microglia might be valuable for treatment. The 18 kDa translocator protein (TSPO), a biomarker of neuroinflammation, is significantly elevated in activated microglia. However, the role of TSPO in microglia activation has not been well demonstrated. In this study, we evaluated the role of TSPO and its ligands PK11195 and Midazolam in LPS-activated BV-2 microglia cells involving mitophagy process and the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation. In the microglia-neuron coculture system, the neurotoxicity induced by LPS-activated microglia and the neuroprotective effects of PK11195 and Midazolam were evaluated. Our results showed that after being stimulated by LPS, the expression of TSPO was increased, and the process of mitophagy was inhibited in BV-2 microglia cells. Inhibition of mitophagy was reversed by pretreatment with PK11195 and Midazolam. And the NLRP3 inflammasome was increased in LPS-activated BV-2 microglia cells in the microglia-neuron coculture system; pretreatment with PK11195 and Midazolam limited this undesirable situation. Lastly, PK11195 and Midazolam improved the cell viability and reduced apoptosis of neuronal cells in the microglia-neuron coculture system. Taken together, TSPO ligands PK11195 and Midazolam showed neuroprotective effects by reducing the inflammatory response of LPS-activated microglia, which may be related to the enhancement of mitophagy and the inhibition of NLRP3 inflammasome.
神经炎症是神经退行性疾病的关键病理过程,减轻异常激活的小胶质细胞引起的炎症反应可能对治疗具有重要价值。18 kDa 转位蛋白(TSPO)是神经炎症的生物标志物,在激活的小胶质细胞中显著升高。然而,TSPO 在小胶质细胞激活中的作用尚未得到充分证明。在这项研究中,我们评估了 TSPO 及其配体 PK11195 和咪达唑仑在 LPS 激活的 BV-2 小胶质细胞中涉及自噬过程和核苷酸结合域样受体蛋白 3(NLRP3)炎症小体激活的作用。在小胶质细胞-神经元共培养系统中,评估了 LPS 激活的小胶质细胞诱导的神经毒性以及 PK11195 和咪达唑仑的神经保护作用。我们的结果表明,在 LPS 刺激后,BV-2 小胶质细胞中 TSPO 的表达增加,自噬过程受到抑制。PK11195 和咪达唑仑预处理可逆转自噬过程。并且 NLRP3 炎症小体在小胶质细胞-神经元共培养系统中 LPS 激活的 BV-2 小胶质细胞中增加;PK11195 和咪达唑仑的预处理限制了这种不良情况。最后,PK11195 和咪达唑仑改善了小胶质细胞-神经元共培养系统中小胶质细胞激活的神经元细胞的活力并减少了细胞凋亡。综上所述,TSPO 配体 PK11195 和咪达唑仑通过减轻 LPS 激活的小胶质细胞的炎症反应表现出神经保护作用,这可能与增强自噬和抑制 NLRP3 炎症小体有关。