Behavioral, biochemical, and molecular characterization of MPTP/p-intoxicated mice

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most extensively utilized animal model for Parkinson's disease (PD). Treatment regimens are classified into three categories: acute, subacute, and chronic. Among these, the MPTP with probenecid (MPTP/p)-induced chronic mouse model is favored for its capacity to sustain long-term striatal dopamine depletion, though the resultant behavioral, biochemical, and molecular alterations require further validation. To systematically evaluate these abnormalities in the chronic MPTP/p mouse model, we conducted observations over a 12-month period. The results showed that these mice displayed reduced locomotor activity, minor gait abnormalities, and anxiety-like behavior within one week following the final MPTP/p injection. No significant motor disorders were observed from 1 to 12 months post-final injection, with exception of increased exploratory activity in the elevated plus maze from 2 to 8 months. One month after the final MPTP/p injection, there was a significant decrease in dopaminergic neurons in the ventral midbrain, which partially recovered after 12 months. A single MPTP/p injection temporarily increased striatal DA and its metabolites. Proteomics of ventral midbrain tissue indicated that the recovery of dopaminergic neurons might be linked to the upregulation of proteins like Bone morphogenetic protein type II receptor (Bmpr2) and Glutathione S-transferase mu 2 (Gstm2) once MPTP toxicity was removed. Our study indicated that the optimal time to evaluate behavioral abnormalities in chronic MPTP/p mouse model is within one week after modeling. Moreover, the upregulated expression of related proteins, such as Bmpr2 and Gstm2, in the ventral midbrain of the model mice after modeling may represent important targets for the future treatment of Parkinson's disease.