Post-treatment with Meloxicam Attenuates MPP⁺-Induced Neurotoxicity via PI3K/Akt-Dependent Maintenance of Mcl-1

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway. Current treatments for PD primarily provide symptomatic relief through dopamine replacement; however, no neuroprotective drugs are currently clinically available. Our previous work demonstrated that meloxicam (MLX) protects against 1-methyl-4-phenylpyridinium (MPP⁺)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, independent of cyclooxygenase inhibition. However, the downstream mechanisms remain unclear. In this study, we examined which anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, including Bcl-2, Bcl-xL, and myeloid cell leukemia 1 (Mcl-1), contribute to MLX-mediated neuroprotection. We also evaluated whether post-treatment with MLX can rescue MPP⁺-induced neurotoxicity, considering its potential clinical applicability. Cell viability assays and Western blotting were performed to assess neuronal survival and protein expression. Our results show that post-treatment with MLX restored neuronal viability after MPP⁺ exposure through the PI3K/Akt/Mcl-1 pathway, indicating that MLX can attenuate MPP⁺-induced apoptotic progression even when administered at delayed time points. These findings elucidate the molecular basis of MLX-mediated neuroprotection and support the potential therapeutic repurposing of MLX as a neuroprotective agent for PD.