Efficacy of TSPO ligands on neuronal damage mediated by LPS-stimulated BV-2 microglial activation

Abstract

Background Neuroinflammation mediated by microglia is an important pathological process of neurodegenerative diseases. Alleviating the inflammatory response caused by activated microglia might be a valuable treatment. The 18-kDa translocator protein (TSPO), as a marker of neuroinflammation, is significantly elevated in activated microglia. But the function of TSPO in microglia has not been well demonstrated. Methods In this study, we evaluated the role of TSPO and its ligands in LPS-activated BV-2 microglia involving mitophagy pathway and the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation. Then, in the microglia-neuron co-culture system, the neurotoxicity induced by LPS-activated microglia and the neuroprotective effects of TSPO ligands were evaluated. Results Our results showed that after stimulated by LPS, TSPO expression was increased, meanwhile the expression of autophagy associated proteins were decreased in BV-2 microglia cells, but the reduction was reversed by pretreatment with PK11195 and Midazolam. Simultaneously, the NLRP3 inflammasome were increased in LPS activated BV-2 microglia in Transwell co-culture system, pretreatment with TSPO ligands could curb this undesirable situation. Furthermore, TSPO ligands improved the cell viability and reduced apoptosis of neuronal cells in co-culture system. Conclusions 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.