Neuroinflammation related to microglial activation plays an important role in neurodegenerative diseases. Translocator protein 18 kDa (TSPO), a biomarker of reactive gliosis, its ligands can reduce neuroinflammation and can be used to treat neurodegenerative diseases. Therefore, we explored whether TSPO ligands exert an anti-inflammatory effect by affecting the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome, thereby inhibiting the release of inflammatory cytokines in microglial cells. In the present study, BV-2 cells were exposed to lipopolysaccharide (LPS) for 6 h to induce an inflammatory response. We found that the levels of reactive oxygen species (ROS), NLRP3 inflammasome, interleukin-1β (IL-1β), and interleukin-18 (IL-18) were significantly increased. However, pretreatment with TSPO ligands inhibited BV-2 microglial and NLRP3 inflammasome activation and significantly reduced the levels of ROS, IL-1β, and IL-18. Furthermore, a combination of LPS and ATP was used to activate the NLRP3 inflammasome. Both pretreatment and post-treatment with TSPO ligand can downregulate the activation of NLRP3 inflammasome and IL-1β expression. Finally, we found that TSPO was involved in the regulation of NLRP3 inflammasome with TSPO ligands treatment in TSPO knockdown BV2 cells. Collectively, these results indicate that TSPO ligands are promising targets to control microglial reactivity and neuroinflammatory diseases.

Delayed neurocognitive recovery (dNCR) is a prevalent perioperative neurological complication in older patients and has common characteristics such as acute cognitive dysfunction, impaired memory, and inattention. Mesenchymal stem cell-derived exosomes (MSCs-Exo) are enclosed by a lipid bilayer contain proteins, DNA, miRNA, and other components, which are important mediators of intercellular communication. It has been reported that exosomes could play an important role in the treatment of neurodegenerative diseases, nerve injury, and other neurological diseases. In this study, we examined the effects of MSCs-Exo on dNCR aged mice after exploratory laparotomy and evaluated their potential regulatory mechanisms. We found that MSCs-Exo treatment ameliorated cognitive impairment in dNCR aged mice. MSCs-Exo inhibit hippocampus ferroptosis and increase the expression of silent information regulator 1 (SIRT1), factor nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in dNCR aged mice. Interestingly, the above effects of MSCs-Exo on dNCR aged mice were abolished by SIRT1 selective inhibitor EX-527. In conclusion, these findings indicated that MSCs-Exo can ameliorate cognitive impairment by inhibiting hippocampus ferroptosis in dNCR aged mice via activating SIRT1/Nrf2/HO-1 signaling pathway, providing a potential avenue for the treatment of dNCR.

Perioperative neurocognitive disorders (PND) is a common postoperative neurological complication. Neuroinflammation is a major cause that leads to PND. Autophagy, an intracellular process of lysosomal degradation, plays an important role in the development and maintenance of nervous system. PK11195 is a classic translocator protein (TSPO) ligand, which can improve the cognitive function of rats. In this study, we evaluate the protective effect of PK11195 on the learning and memory of rats. A rat model of lipopolysaccharide (LPS)-induced cognitive dysfunction was established by intraperitoneal injection of LPS. Morris Water Maze (MWM), Western blot, qRT-PCR, confocal microscopy and transmission electron microscopy (TEM) were used to study the role of TSPO-specific ligand PK11195 in LPS-activated mitochondrial autophagy in rat hippocampus. We found that PK11195 ameliorated LPS-induced learning and memory impairment, as indicated by decreased escape latencies, swimming distances and increased target quadrant platform crossing times and swimming times during MWM tests. TSPO, ATG7, ATG5, LC3B and p62 protein and mRNA expression increased in the hippocampus of PND model rats. The hippocampal microglia of PND model rats also have severe mitochondrial damage, and a large number of autophagosomes and phagocytic vesicles can be seen. PK11195 pretreatment significantly decreased the expression of TSPO, ATG7, ATG5, LC3B and p62 protein and mRNA, as well as mitochondrial damage. These findings suggested that PK11195 may alleviate the damage of LPS-induced cognitive dysfunction of rats by inhibiting microglia activation and autophagy.

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.

Chronic pain is an enormous modern public health problem, with significant numbers of people debilitated by chronic pain from a variety of etiologies. Translocator protein 18 kDa (TSPO) was discovered in 1977 as a peripheral benzodiazepine receptor. It is a five transmembrane domain protein, mainly localized in the outer mitochondrial membrane. Recent and increasing studies have found changes in TSPO and its ligands in various chronic pain models. Reversing their expressions has been shown to alleviate chronic pain in these models, illustrating the effects of TSPO and its ligands. Herein, we review recent evidence and the mechanisms of TSPO in the development of chronic pain associated with peripheral nerve injury, spinal cord injury, cancer, and inflammatory responses. The cumulative evidence indicates that TSPO-based therapy may become an alternative strategy for treating chronic pain.