BACKGROUND: This study explored the protective effects of kaempferol (KAE) against neurotoxicity caused by microglial activation and its underlying mechanisms.
METHODS: Microglia BV2 cells were directly stimulated by LPS to assay the effect of KAE. More, C57BL/6 N mice received intraperitoneal LPS injections to prepare a mouse model of neuroinflammation. Autophagy inhibitors 3-MA and Mdivi-1 were utilized to evaluate the effect of KAE on mitophagy.
RESULTS: The results demonstrated that KAE effectively suppressed LPS-induced the production of inflammatory factors, cell proliferation, phagocytic activity and NF-ĪŗB signaling activation in microglia BV2 cells, showing the inhibitory effects on microglial activation and inflammation response. Mechanically, the ability of KAE to inhibit NLRP3 inflammasome activation was associated with its enhancement of mitophagy to reduce mitochondrial DNA (mtDNA) resynthesis and leakage. Inhibition of mitophagy significantly promotes mtDNA resynthesis and release, almost completely counteracting this anti-inflammatory effect of KAE. Next, we demonstrated that KAE treatment protected neurons against LPS-induced microglial neurotoxicity and attenuated depressive-like behavior in neuroinflammation mice. This effect was associated with the interference of KAE on NLRP3 inflammasomes activation mediated by reduced mitophagy in microglia, suggesting that promoting mitophagy was one of the mechanisms by which KAE exerted neuroprotective effects on neuroinflammatory mice.
CONCLUSION: This study showed that KAE exerted neuroprotective effects by inhibiting LPS-induced neuroinflammation mediated by microglial activation. The underlying mechanism was that KAE promoted mitophagy in microglia exposed to LPS, thereby inhibiting mtDNA leakage-induced NLRP3 inflammasome activation. It pointed to KAE as a promising therapeutic candidate for neuroinflammation-related diseases.
