SVHRSP protects against rotenone-induced neurodegeneration in mice by inhibiting TLR4/NF-κB-mediated neuroinflammation via gut microbiota

Strong evidence indicates that remodeling gut microbiota may be an effective approach to combat Parkinson's disease (PD). Scorpion Venom Heat-Resistant Synthesized Peptide (SVHRSP), a synthesized peptide discovered from scorpion venom, displays potent neuroprotection in multiple PD models. However, the potential mechanisms remain unclear. In this study, we demonstrated that SVHRSP effectively attenuated gastrointestinal function impairments and reinstated the microbiota composition in rotenone-induced PD mouse model. Microbiota depletion and FMT verified that the restored gut microbiota was necessary for SVHRSP-mediated neuroprotection against dopaminergic neurodegeneration in rotenone PD mice. Furthermore, SVHRSP gut microbiota-dependently attenuated BBB impairment, microglial activation, and gene expression of pro-inflammatory factors in rotenone-treated mice. Mechanistically, SVHRSP decreased the concentrations of LPS and HMGB1 in both serum and brain tissue, thereby inhibiting the TLR4/NF-κB signaling pathway in the brain of rotenone-treated mice. Together, our findings provided fresh perspectives on the mechanisms underlying SVHRSP-induced neuroprotection in PD.