OBJECTIVE:  To investigate the effects of inducer of autophagy-Rapamycin on the functional and morphological outcome in a mice model of Parkinson s disease (PD)  rendered by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). BACKGROUND:  Autophagy, a tightly regulated catabolic process involved in the cell metabolism through the lysosomal machinery, plays a role in cell regulation and is a major mechanism. In neurodegenerative disorders such as PD, autophagy participates in the cell death process of dopaminergic neuron. However, the underlying mechanisms for autophagy are not fully understood. α-Synuclein is one of the major components of Lewy bodies and Lewy neuritis and mutation of α-synuclein such as a-synuclein mutants (A53T and A30P) may be involved in the development of familial PD. Dopaminergic loss and inclusion body formation have been implicated for neurodegenerative disorders. Our previous study demonstrated that Rapamycin may induce autophagy and decrease aggregation of α-synuclein and cell death. DESIGN/METHODS: Male C57BL mice were treated with rapamycin(3mg/kg) by i.v bolus for 7 days after MPTP administration(30mg/kg.14d), and were compared with saline-treated PD mice and normal control group. Immunohistochemistry and Western blot were used to detect the alterations of PD biomarker including tyrosine hydroxylase (TH),  and  the level of autophagy was investigated by microtubule-associated protein light chain 3(LC3) and α-synuclein cleavage. In addition, monoamine neurotransmitters in the striatum of mice were measured by the high performance liquid chromatography (HPLC).

RESULTS: TH immunohistochemistry indicated that the number of dopaminergic neurons in the substantia nigra was increased in Rapamycin-treated mice compared with saline-treated mice(p<0.01). Western blot demonstrated the similar TH protein expression in striatum. α-synuclein was markedly decreased in rapamycin-treated mice compared with the NS-treated mice(p<0.01), meanwhile, LC3 was markedly increased in rapamycin-treated mice compared with the NS-treated mice(p<0.01). The concentrations of striatal dopamine and its metabolite DOPAC compared to the normal mice were decreased significantly in other groups. Rapamycin-treated mice minimized the reduction of DOPAC compared with the NS-treated mice(p<0.01). CONCLUSIONS/RELEVANCE:  These results showed that Rapamycin is able to rescue the dopaminergic neurons in different doses and reverses the loss of DOPAC through activation of autophagy-lysosome pathway, and it may be a promising therapeutic agent in PD. A better understanding of the underlying mechanisms for α-synuclein-mediated neurodegeneration may provide novel targets for the discovery of new therapies for PD and related neurodegenerative α-synucleinopathies.

[Key words]  Rapamycin; MPTP; Parkinson’s disease; autophagy