Diosgenin derivative ML5 attenuates MPTP-induced neuronal impairment via regulating AMPK/PGC-1α-mediated mitochondrial biogenesis and fusion/fission.

Objective: The aim of the present study was to assess the therapeutic impact of diosgenin derivative ML5 on Parkinson's disease (PD) and explore the mechanism underlying mitochondrial biogenesis and fusion/fission.

Methods: We established 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models and N-methyl-4-phenylpyridinium iodide (MPP)-induced cell models of PD. The pole test and forced swimming test were used to detect the motor coordination and depressive symptoms in mice. The influence of ML5 on dopaminergic neuronal injury was investigated. Meanwhile, adenosine triphosphate (ATP) content, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) production were measured to evaluate mitochondrial function. Confocal and transmission electron microscopy were used to detect mitochondrial morphology of cell. The expression of mitochondrial biogenesis-related proteins was measured by Western blotting.

Results: The administration of ML5 showed the neuroprotection against MPTP-induced damage and . The levels of ATP, MMP, and ROS were restored after ML5 administration. In addition, we observed that ML5 preserved the mitochondrial network morphology and inhibited mitochondrial fission. Furthermore, the amelioration of mitochondrial dysfunction was mediated by enhancing 5'-monophosphate-activated protein kinase (AMPK) and peroxisome proliferators-activated receptor γ coactivator-l alpha (PGC-1α) expression, which activated its downstream modulators leading to the enhancing of mitochondrial biogenesis and the balance of mitochondrial fusion/fission.

Conclusion: ML5 can protect the PD models against MPTP/MPP-induced mitochondrial dysfunction and neuronal injury via promoting AMPK/PGC-1α signaling activation and be used as a therapeutic drug for PD treatment.