TSPO Ligands Protect against Neuronal Damage Mediated by LPS-Induced BV-2 Microglia Activation.
TSPO Ligands Protect against Neuronal Damage Mediated by LPS-Induced BV-2 Microglia Activation.
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DOI：
10.1155/2022/5896699
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发表时间：
2022
影响因子：
--
通讯作者：
Feng J
中科院分区：
文献类型：
--
作者：
Ma B;Liu Y;Zhang X;Zhang R;Zhang Z;Zhang Z;Liu J;Juan Z;Sun X;Sun L;Huang J;Feng J
神经炎症是神经退行性疾病的重要病理过程，减轻小胶质细胞异常激活引起的炎症反应可能对治疗有价值。18 kDa转运蛋白（TSPO），神经炎症的生物标志物，在活化的小胶质细胞中显著升高。然而，TSPO在小胶质细胞活化中的作用尚未得到很好的证实。在这项研究中，我们评估了TSPO及其配体PK 11195和咪达唑仑在LPS激活的BV-2小胶质细胞中的作用，涉及线粒体吞噬过程和核苷酸结合结构域样受体蛋白3（NLRP 3）炎性小体激活。在小胶质细胞-神经元共培养系统中，观察LPS激活的小胶质细胞对神经元的毒性作用，以及PK 11195和咪达唑仑对神经元的保护作用。结果表明，LPS刺激后BV-2小胶质细胞TSPO表达增加，线粒体自噬过程受到抑制。用PK 11195和咪达唑仑预处理可逆转对线粒体自噬的抑制。在小胶质细胞-神经元共培养系统中，LPS激活的BV-2小胶质细胞中的NLRP 3炎性小体增加;用PK 11195和咪达唑仑预处理限制了这种不良情况。最后，PK 11195和咪达唑仑在小胶质细胞-神经元共培养系统中提高细胞活力并减少神经元细胞凋亡。总之，TSPO配体PK 11195和咪达唑仑通过减少LPS激活的小胶质细胞的炎症反应而显示出神经保护作用，这可能与增强线粒体自噬和抑制NLRP 3炎性体有关。
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.
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DOI：
10.1016/s2215-0366(20)30255-8
发表时间：
2020-12
期刊：
The lancet. Psychiatry
影响因子：
--
作者：
Meyer JH;Cervenka S;Kim MJ;Kreisl WC;Henter ID;Innis RB
通讯作者：
Innis RB
影响因子：
29.7
作者：
Nayak D;Roth TL;McGavern DB
通讯作者：
McGavern DB
影响因子：
13.5
作者：
Harry, G. Jean
通讯作者：
Harry, G. Jean
影响因子：
5.3
作者：
Papadopoulos, Vassilios;Lecanu, Laurent
通讯作者：
Lecanu, Laurent
影响因子：
13.5
作者：
Guilarte TR
通讯作者：
Guilarte TR