Inhibition of NLRP3 inflammasome ameliorates LPS-induced neuroinflammatory injury in mice via PINK1/Parkin pathway.

Parkinson's disease (PD) is characterized by the severe loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor dysfunction. The onset of PD is often accompanied by neuroinflammation and α-Synuclein aggregation, and extensive research has focused on the activation of microglial NLRP3 inflammasomes in PD, which promotes the death of dopaminergic neurons. In this study, a model of cerebral inflammatory response was constructed in wild-type and Parkin ^＋/－ mice through bilateral intraventricular injection of LPS. LPS-induced activation of the NLRP3 inflammasome in wild-type mice promotes the progression of PD. The use of MCC950 in wild mice injected with LPS induces activation of Parkin/PINK and improves autophagy, which in turn improves mitochondrial turnover. It also inhibits LPS-induced inflammatory responses, improves motor function, protects dopaminergic neurons, and inhibits microglia activation. Furthermore, Parkin ^＋/－ mice exhibited motor dysfunction, loss of dopaminergic neurons, activation of the NLRP3 inflammasome, and α-Synuclein aggregation beginning at an early age. Parkin ^± mice exhibited more pronounced microglia activation, greater NLRP3 inflammasome activation, more severe autophagy dysfunction, and more pronounced motor dysfunction after LPS injection compared to wild-type mice. Notably, the use of MCC950 in Parkin ^± mice did not ameliorate NLRP3 inflammasome activation, autophagy dysfunction, or α-synuclein aggregation. Thus, MCC950 can only exert its effects in the presence of Parkin/PINK1, and targeting Parkin-mediated NLRP3 inflammasome activation is expected to be a potential therapeutic strategy for Parkinson's disease.
Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All authors read and approved the final manuscript.
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