8-Gingerol Mitigates MPP⁺-Induced α-Synuclein Aggregation and NLRP3 Inflammasome Activation by Inducing the Insulin Signaling Pathway in SH-SY5Y Cells

Impaired insulin signaling facilitates α-synuclein aggregation and exacerbates neuroinflammation related to Parkinson’s disease (PD). This study investigated whether 8-gingerol from ginger could protect against MPP⁺-induced α-synuclein aggregation and neuroinflammation in SH-SY5Y cells via the insulin signaling pathway. MTT assay showed that MPP⁺ markedly reduced SH-SY5Y cell viability at 0.5-2 mM. Treatment of cells with 6-gingerol and 8-gingerol, but not 6-shogaol, significantly attenuated MPP⁺-induced cytotoxicity. The concentration at 20 µM showed the strongest neuroprotective effect. Immunoblots showed that 8-gingerol treatment attenuated the accumulation of ^Ser129p-α-synuclein and ^Thr231p-Tau induced by MPP⁺ for 24 h. Furthermore, 8-gingerol normalized the aberrant phosphorylation of IRS-1, Akt, and GSK-3β induced by MPP⁺. It also suppressed the MPP⁺-induced expression of inflammasome-associated proteins, including FoxO1, TXNIP, NLRP3, and cleaved-caspase 1. Pre-treatment with the PI3K/Akt inhibitor wortmannin abrogated the protective effects by increasing ^Ser129p-α-synuclein and NLRP3 inflammasome protein levels. These results indicated that 8-gingerol protects SH-SY5Y cells against MPP⁺-induced the α-synuclein aggregation and NLRP3 inflammasome activation is mediated through the insulin signaling pathway.