Dopaminergic and behavioral correlates of progressive lesioning of the nigrostriatal pathway with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

A number of neurotoxin- and gene-based rodent models of acute neurodegeneration of nigrostriatal dopamine (DA) neurons are used to study Parkinson's disease (PD). The rapid degeneration achieved by many of these current models limits the capacity of the model to develop pathogenic mechanisms and display the various stages of motor degradation representative of the human Parkinsonian condition. Chronic rodent models have been the only ones to reproduce these characteristics, yet do not show correlated progress of DA loss with multiple stepwise behavioral deficits as seen in humans. In the present study, we have developed a progressive model of increasing DA loss and motor dysfunction via progressively increased administration of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in the C57Bl/6J mouse. Mice were administered a daily (5 d/wk) dose of MPTP that increased weekly over the course of 4 weeks (4 mg/kg, 8 mg/kg, 16 mg/kg and 32 mg/kg). Each treatment group was tested for exploratory and motor behavioral changes after every week leading up to their final dose, as well as changes in tyrosine hydroxylase immunoreactivity (TH-ir) of the substantia nigra pars compacta (SNpc) and caudate putamen (CPu). We detected a 24% decrease in the mean number of TH-ir SNpc neurons/section after 1 week, and a 62% decrease after 4 weeks as compared to the vehicle group. CPu TH-ir began at a 35% loss after 1 week and increased to a 74% loss after 4 weeks compared to the vehicle group. CPu DA content showed an initial decrease of 20% after 1 week, and a final decrease of 70% following week 4 versus the vehicle group. Free-standing rears (versus wall-assisted rears, in a cylinder), decreased from 35% to 8% of total rears as the dose of MPTP increased from 4 mg/kg to 32 mg/kg, respectively. However, motor impairment as measured by a Parallel Rod Activity Chamber test was not significant until week 4 at 32 mg/kg compared to the vehicle group. The present study is the first to show stepwise progression of behavioral deficits which correlate with gradual dopaminergic decline in the nigrostriatal pathway. This progressive lesioning regiment may be appropriate for future investigation of pathogenic mechanisms and various intervention therapies in PD.

Enriched environment promotes similar neuronal and behavioral recovery in a young and aged mouse model of Parkinson's disease.

Environmental enrichment has been shown to be neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD). Because PD patients are not typically diagnosed until later neuropathological stages, the current study investigated the capacity of an enriched environment (EE) to stimulate restoration of neurons in the substantia nigra pars compacta (SNpc) and locomotor recovery after lesioning, as opposed to before. A low-dose chronic MPTP regimen was used to achieve a partial, less severe lesion of the nigrostriatal pathway not seen in acute MPTP models. Both young adult (10 weeks) and aged (12 months) C57BL/6J male mice were used to assess the effects of aging on recovery with EE intervention. After the first week of either MPTP (7 mg/kg/d in young; 5 mg/kg/d in aged) or saline injection, animals from both groups were housed in a standard environment (SE) or an EE for 3 weeks, with continued daily administration of MPTP. We are the first to report that following 3 weeks exposure to an EE, young and aged MPTP-lesioned mice showed a significant 53% and 52% restoration of tyrosine hydroxylase (TH)-labeled neurons in the SNpc, respectively. This increase in TH-labeled cells in the MPTP+EE group was correlated with recovery of free-standing rear (FSR) behavior in both age groups; however, improved locomotor control as measured by foot faults (FF) per total activity was only seen in the aged MPTP+EE group. Our data demonstrate that an EE promotes neurorestoration in TH protein expression in SNpc neurons as well as some locomotor recovery in both young and aged animals in this mouse model of PD.