Differences between subacute and chronic MPTP mice models: investigation of dopaminergic neuronal degeneration and α‐synuclein inclusions

Abstract Animal models are invaluable tools to study neurodegenerative disorders but a general consensus on the most accurate rodent model of Parkinson’s disease has not been reached. Here, we examined how different methods of MPTP administration influence the degeneration of the dopaminergic (DA) system. Adult male C57BL/6 mice were treated with the same cumulative dose of MPTP following four distinct procedures: (i) subacute i.p. injections; (ii) 28‐day chronic s.c. infusion; (iii) 28‐day chronic i.p. infusion; and (iv) 14‐day chronic i.p. infusion. Subacute MPTP treatment significantly affected all aspects of the DA system within the nigral and striatal territories. In contrast, the 28‐day chronic s.c. infusion did not significantly alter any components of the DA system. The 28‐ and 14‐day chronic i.p. infusions induced loss of tyrosine hydroxylase (TH)‐positive cells correlated with a decrease in Nurr1 mRNA levels, but no significant decrease in the density of TH striatal fibers. Importantly, however, only the 14‐day chronic MPTP i.p. infusion protocol promoted the formation of neuronal inclusions as noted by the expression of α‐synuclein protein within the cytoplasm of TH nigral neurons. Overall, we found that the 14‐day chronic MPTP i.p. infusion reproduces more accurately the pathological characteristics of early stage Parkinson’s disease.