Neuroprotective Effect of Mangiferin against Parkinson’s Disease through G-Protein-Coupled Receptor-Interacting Protein 1 (GIT1)-Mediated Antioxidant Defense

Parkinson's disease (PD), known as a neurodegenerative disease, is characterized by movement disorders, with increasing age being the predominant risk factor for its development. Mangiferin, a bioactive compound isolated from mango, shows potent neuroprotection. In our work, we investigated the neuroprotection and mechanisms of mangiferin against PD. We established PD models by treating SH-SY5Y cells with rotenone and mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and investigated the therapeutic effects of mangiferin. Our results showed that mangiferin exhibited a cell-protective effect. Mangiferin also improved the motor behavior and attenuated the activation of microglia and astrocytes in MPTP mice. In addition, mangiferin decreased reactive oxygen species (ROS) levels and increased glutathione (GSH) and superoxide dismutase (SOD). Mangiferin also markedly activated GIT1, p-ERK, Nrf2, HO-1, and SOD expression and inhibited Keap1 expression in vitro and in vivo. To further investigate the role of GIT1, GIT1 siRNA was used. In the presence of GIT1 siRNA, the neuroprotection of mangiferin in PD was weakened. Our results indicate that mangiferin exhibited its therapeutic effect against PD by regulating GIT1 and its downstream Keap1/Nrf2 pathways. Our studies exhibited that mangiferin showed neuroprotection in PD, and its main target was GIT1. What is more, mangiferin could reduce the oxidative stress of PD by targeting GIT1 and its downstream Keap1/Nrf2 pathways. These indicated that mangiferin is a good candidate for PD therapy. However, the role of p-ERK in mangiferin-treated PD requires further investigation.