Objective To investigate the possible effect of silent information regulator 1 (SIRT1) and p53 in loss of dopaminergic neuronsinduced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in a mouse model of Parkinson's disease (PD).Methods Healthy male C57BL/6 mice were randomly divided into control group and MPTP group. Behavioral test was conducted to observe behavioral changes; high-performance liquid chromatography (HPLC) was used to measure the changes in the levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA); immunofluorescent staining was used to observe the change in the number of tyrosine hydroxylase (TH)-positive neurons and the expression of SIRT1 in substantia nigra; the TUNEL method was used to observe cell apoptosis in the substantia nigra; Western blot was used to measure the expression of TH, SIRT1, p53, acetylated p53 (ac-p53),B-cell lymphoma-2 (Bcl-2), and Bax.Results The behavioral analysis showed that compared with the control group, the MPTP group had longer turning time and total pole-climbing time in pole-climbing test (P<0.01). HPLC results showed that the MPTP group had significantly lower levels of DA, DOPAC, and HVA than the control group (P<0.01). Immunofluorescence assay showed that compared with the control group, the MPTP group had significantly lower number of TH-positive neurons and expression of SIRT1 in the substantial nigra. The TUNEL results showed that the MPTP group had a significantly higher number of apoptosis-positive cells than the control group. Western blot showed that compared with the control group, the MPTP group had significant reductions in the protein expression of TH, SIRT1, and Bcl-2 (P<0.01) and significant increases in the protein expression of p53, ac-p53, and Bax (P<0.01).Conclusions Behavioral abnormalities, reduction in TH-positive neurons, and reductions in DA and its metabolites in MPTP model mice suggest that the animal model of PD is successfully established. Abnormal expression of SIRT1, p53, and apoptosis-related proteins in MPTP model mice indicates that the SIRT1/p53 signaling pathway may be involved in the development of PD.