β-Hydroxybutyrate alleviates pyroptosis in MPP+/MPTP-induced Parkinson's disease models via inhibiting STAT3/NLRP3/GSDMD pathway

Background: Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor symptoms and non-motor symptoms, and affects millions of people worldwide. Growing evidence implies beta-Hydrox-ybutyrate (BHB), one of the ketone bodies generated by ketogenesis, plays a neuroprotective role in neurode-generative diseases. We aimed to verify the anti-inflammatory effect of BHB on PD and further explore potential molecular mechanisms.Methods: We performed the experiments on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model in vivo and 1-methyl-4-phenylpyridinium (MPP+)-simulated BV2 cell model in vitro, with or without BHB pretreatment. Motor function was assessed by pole test, forced swimming test, traction test and open field test. Immunofluorescence was used to evaluate the loss of dopaminergic neurons and glial cell activation in MPTP-induced PD model mice. The expression of the STAT3/NLRP3/GSDMD signal pathway was measured by west-ern blots. Proinflammatory cytokines was assessed by enzyme-linked immunosorbent assay (ELISA). Results: BHB treatment reversed motor deficits, loss of dopaminergic neurons and glial cell activation in PD mice induced by MPTP. Moreover, BHB inhibited microglia pyroptosis by negatively regulating STAT3/NLRP3/ GSDMD signal pathway, resulting in downregulation of proinflammatory cytokines (IL-1 beta and IL-18) in vivo and vitro.Conclusion: These data suggested BHB supplement inhibited pyroptosis by down-regulating STAT3-mediated NLRP3 inflammasome activation for PD models in vivo and in vitro. Our findings provided novel insights and available interventions for the prevention and treatment of PD, and highlighted pyroptosis as a potential ther-apeutic target for PD.