Behavioral, Biochemical and Molecular Characterization of a Parkinson’s Disease Mouse Model Using the Neurotoxin 2′-CH3-MPTP: A Novel Approach

Abstract

The neurotoxin MPTP has long been used to create a mouse model of Parkinson's disease (PD). Indeed, several MPTP analogues have been developed, including 2'-CH-MPTP, which was shown to induce nigrostriatal DA neuronal depletion more potently than MPTP. However, no study on behavioral and molecular alterations in response to 2'-CH-MPTP has been carried out so far. In the present work, 2'-CH-MPTP was administered to mice (2.5, 5.0 and 10 mg/kg per injection, once a day, 5 days) and histological, biochemical, molecular and behavioral alterations were evaluated. We show that, despite a dose-dependent-like pattern observed for nigrostriatal dopaminergic neuronal death and dopamine depletion, dose-specific alterations in dopamine metabolism and in the expression of dopaminergic neurotransmission-associated genes could be related to specific motor deficits elicited by the different doses tested. Interestingly, 2'-CH-MPTP leads to increased DAT and MAO-B transcription, which could explain, respectively, its higher potency and the requirement of higher doses of MAO inhibitors to prevent nigrostriatal neuronal death when compared to MPTP. Also, perturbations in dopamine metabolism as well as possible alterations in dopamine bioavailability in the synaptic cleft were also identified and correlated with strength and ambulation deficits in response to specific doses. Overall, the present work brings new evidence supporting the distinct effects of 2'-CH-MPTP when compared to its analogue MPTP. Moreover, our data highlight the utmost importance of a precise experimental design, as different administration regimens and doses yield different biochemical, molecular and behavioral alterations, which can be explored to study specific aspects of PD.

Olive oil limited motor disruption and neuronal damage in parkinsonism induced by MPTP administration

“…18 However, in this work, the diminished performance in open-field and rotarod tests allowed to notice the limited coordination within several days of evaluation; although muscle strength loss was noticeable within the first hours, 31 it recovered faster than coordination, as it is often described when MPTP or analogues are used to induce motor disruption. 27,32,33 This observation requires special attention as muscle strength is related to different neuronal networks and nuclei from those related to coordinated movements of the limbs. 34 Additional studies are required to establish if the damage is a partial judging from the behavioral evaluation.…”