Objective:To investigate the acute damage of the nigrastriatal system in SAMP8 mouse after treatment with MPTP and its relationship with microglial activation.Methods: Totally 57 male SAMP8 mice were randomly divided into two groups,control group and MPTP group.Mice were sacrificed (each time 6-9 mice) at 6 h,24 h,3 d,and 8 d after the first injection in each group.Mice were subcutaneously injected with normal saline or MPTP (20 mg/kg) at an interval of 2 h for 4 times.The changes of spontaneous activity of mice were observed after injection.The changes of TH+ (tyrosine hydroxylase positive) neuronal numbers in the substantial nigra,TH-ir (tyrosine hydroxylase immunoreactivity), and microglial activation in striatum were examined by immunohistochemistry; striatal dopamine (DA) levels were determined by HPLC.Results: The spontaneous activity of SAMP8 mice was decreased significantly after the third injection,and recovered at 48 h after the first injection. Compared with the control group,the TH+ neurons in MPTP group decreased by 7.06% at 6 hours (P=0.235),by 12.79% at 24 hours(P<0.05),by 22.49% at 3 days(P<0.01),and by 42.39% at 8 days(P<0.001); there was significant difference in the TH+ neurons between the 3 days and 8 days (P<0.05).The corrected optical densities (COD) of TH-ir in the striatum in MPTP group were significantly lower than those in the control group at different time points (6 h,\[P<0.05\],24 h\[P<0.01\],3 d\[P<0.001\],8 d\[P<0.001\]); there was significant difference between the 24 h and 3 days groups (P<0.05).Compared with the control group,the striatal dopamine (DA) levels decreased by 79.09% at 6 hours ( P<0.001),by 80.3% at 24 hours (P<0.001),by 86.6% at 3 days (P<0.001),and by 81.0% at 8 days (P<0.001); there were no significant difference between the 24 h,3 days,and 8 days.The immunoreactivity of microglial greatly increased at 24 hours,further activated at 3 days,and largely abated at 8 days after MPTP injection.Conclusion: MPTP can cause acute damage to substantia nigra of SAMP8 mice,resulting in reduced spontaneous activity and dopaminergic neurons loss; the activation of microglial might be related to the nigrostriatum damage of MPTP-SAMP8 mice.