MANF improves the MPP⁺/MPTP-induced Parkinson's disease via improvement of mitochondrial function and inhibition of oxidative stress

Objective: This study aimed to investigate the therapeutic effect of mesencephalic astrocyte-derived neurotrophic factor (MANF) on the MPTP/MPP⁺-induced model of Parkinson's disease (PD) and the potential mechanism.

Methods: Male C57BL/6 mice PD model with MPTP-induced were randomly injected bilaterally with MANF or PBS into the striatum. Two weeks later, Rotarod test, immunohistochemistry, and detection of dopamine (DA) and its metabolites, superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) were performed. A cell model of PD was established by incubating SH-SY5Y cells with MPP⁺, cells were pretreated for 2 h with different concentrations of MANF before 24 h incubation with MPP⁺. Cell viability, expression of Bax, and Bcl-2, gene expression levels of Heme oxygenase 1 (HMOX1) and Superoxide dismutase 2 (SOD2), and mitochondrial transmembrane potential were detected.

Results: The latency reduction in PD mice was partially restored after MANF treatment (P<0.05); MANF significantly reduced the loss of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra pars compacta (SNpc) (P<0.01); MANF significantly increased the striatal DA level in PD mice (P<0.05) and markedly increased the SOD activity (P<0.01) and GSH production (P<0.01). MANF pre-treatment significantly decreased the MPP⁺-induced reduction of cell viability (P<0.01), inhibited the ratio of Bax/Bcl-2 expression (P<0.01), activated gene expression levels of HMOX1 (P<0.01) and SOD2 (P<0.05), and reversed MPP⁺-induced loss of mitochondrial membrane potential (P<0.01).

Conclusion: MANF can attenuate the neuronal lesion in MPTP/MPP⁺-induced PD mice, which may be related to the improvement of mitochondrial function and inhibition of oxidative stress.