Neurochemical, histological, and behavioral profiling of the acute, sub‐acute, and chronic MPTP mouse model of Parkinsonʼs disease

Abstract

Parkinson's disease (PD) is a heterogeneous multi-systemic disorder unique to humans characterized by motor and non-motor symptoms. Preclinical experimental models of PD present limitations and inconsistent neurochemical, histological, and behavioral readouts. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD is the most common in vivo screening platform for novel drug therapies; nonetheless, behavioral endpoints yielded amongst laboratories are often discordant and inconclusive. In this study, we characterized neurochemically, histologically, and behaviorally three different MPTP mouse models of PD to identify translational traits reminiscent of PD symptomatology. MPTP was intraperitoneally (i.p.) administered in three different regimens: (i) acute-four injections of 20 mg/kg of MPTP every 2 h; (ii) sub-acute-one daily injection of 30 mg/kg of MPTP for 5 consecutive days; and (iii) chronic-one daily injection of 4 mg/kg of MPTP for 28 consecutive days. A series of behavioral tests were conducted to assess motor and non-motor behavioral changes including anxiety, endurance, gait, motor deficits, cognitive impairment, circadian rhythm and food consumption. Impairments in balance and gait were confirmed in the chronic and acute models, respectively, with the latter showing significant correlation with lesion size. The subacute model, by contrast, presented with generalized hyperactivity. Both, motor and non-motor changes were identified in the acute and sub-acute regime where habituation to a novel environment was significantly reduced. Moreover, we report increased water and food intake across all three models. Overall, the acute model displayed the most severe lesion size, while across the three models striatal dopamine content (DA) did not correlate with the behavioral performance. The present study demonstrates that detection of behavioral changes following MPTP exposure is challenging and does not correlate with the dopaminergic lesion extent.

Peripheral MC1R Activation Modulates Immune Responses and is Neuroprotective in a Mouse Model of Parkinson’s Disease

“…For primary outcome measures, the mice were sacrificed at 12 days after the last MPTP dosing. The end timepoint was based on the established subacute MPTP regimen, which induces DA deficits 7–21 days (Chen et al 2017a ; Jackson-Lewis and Przedborski 2007 ; Santoro et al 2023 ) and a MPTP + LPS mouse model, which induces DA deficits 2 weeks post-MPTP injection (García-Domínguez et al 2018 ).…”