α -Lipoic acid alleviates Parkinson's disease by suppressing S100A9-mediated pyroptosis.

Parkinson's disease (PD) is a neurodegenerative disease, and inflammation is a key factor in the progression of PD. S100A9 mediates pyroptosis and implicates in various diseases including PD. Pyroptosis, an emerging form of programmed cell death, usually causes cell rupture and death via an inflammatory response. α-Lipoic acid (α-ALA), a cellular coenzyme, participates in anti-inflammatory and antioxidant processes. Although its role in PD has been confirmed, but the exact mechanism of its anti-inflammatory effect remains unclear. In our research, we examined the potential mechanisms of pyroptosis mediated by S100A9 in PD and the neuroprotective effects of α-ALA. We used 6-hydroxydopamine (6-OHDA) to induce SH-SY5Y cells in vitro and in C57BL/6 mice in vivo. The cell viability of SH-SY5Y cells confirmed the neuroprotective effect of α-ALA. Proteomics analysis indicated that S100A9 was involved in 6-OHDA-mediated neuronal injury, while α-ALA could inhibit. We found that α-ALA ameliorated PD symptoms induced by 6-OHDA and decreased the levels of NLRP3 inflammasome, Gasdermin D, and IL-1β, which are major hallmarks of pyroptosis. Furthermore, our research demonstrated that α-ALA mitigated cell injury by suppressing NLRP3-dependent pyroptosis mediated by S100A9. In brief, pyroptosis is pivotal in PD, while α-ALA protects dopaminergic neurons by suppressing pyroptosis mediated through the NLRP3 inflammasome, directly reducing S100A9, and subsequently inhibiting the NLRP3/Gasdermin D signaling pathways. Our results collectively suggest that suppressing S100A9-mediated pyroptosis and administering α-ALA may represent a novel approach in treating of PD.