MPTP Mouse Model of Preclinical and Clinical Parkinson’s Disease as an Instrument for Translational Medicine

Abstract

Parkinson's disease (PD) is characterized by the appearance of motor symptoms many years after the onset of neurodegeneration, which explains low efficiency of therapy. Therefore, one of the priorities in neurology is to develop an early diagnosis and preventive treatment of PD, based on knowledge of molecular mechanisms of neurodegeneration and neuroplasticity in the nigrostriatal system. However, due to inability to diagnose PD at preclinical stage, research and development must be performed in animal models by comparing the nigrostriatal system in the models of asymptomatic and early symptomatic stages of PD. In this study, we showed that despite the progressive loss of neurons in the substantia nigra at the presymptomatic and symptomatic stage, almost no change was observed in the main functional characteristics of this brain region, including dopamine (DA) uptake and release, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) expression, and activity of MAO-A and MAO-B. In the striatum of presymptomatic mice, some parameters (DA release and uptake, MAO-A activity) remained compensatory unchanged or compensatory decreased (MAO-B gene expression and activity), while others-a reduction in DA levels in tissue and extracellular space and in VMAT2 and DAT expression-manifest the functional failure. In symptomatic mice, only a few parameters (spontaneous DA release and uptake, MAO-B gene expression and activity) remained at the same level as at presymptomatic stage, while most parameters (DA level in tissue and extracellular space, DA-stimulated release, VMAT2 and DAT contents), decreased, showing decompensation, which was enhanced by increasing MAO-A activity. Thus, this study provides a comprehensive assessment of the molecular mechanisms of neuroplasticity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine models of preclinical and clinical stages of PD, which could potentially serve as a powerful tool for translational medicine.

Sophora Tomentosa Extract Prevents MPTP-Induced Parkinsonism in C57BL/6 Mice Via the Inhibition of GSK-3β Phosphorylation and Oxidative Stress

“…MPP + is selectively transported by the dopamine transporter (DAT) into dopaminergic neurons in the SN rather than those in the ventral tegmental area because there is a higher density of DAT in the midbrain, which is then damaged by the dopaminergic neurons in the SN. Hence, the administration with MPTP mainly caused a decrease in the density of TH in the nigrostriatal pathway and led to a loss of projecting striatal dopaminergic nerve terminal markers—dopamine and its metabolites—in C57BL/6 mice [14,30]. Our present results found that subacute administration with MPTP decreased the density of TH-positive dopaminergic neurons in SN and the expression of TH in the striatum compared to normal mice.…”

“…The appearance of these above motor symptoms in PD is the result of the selective progressive degeneration of the dopaminergic neurons in the SN and the depletion of projecting dopaminergic nerve fibers in the striatum up to a threshold level. According to clinical reports, motor symptoms first appear in PD patients at a loss of 50–60% of dopaminergic neurons in the SN and 70–80% depletion of dopamine levels in the striatum [1,30]. MPTP is converted to MPP + via monoamine oxidase B (MAO-B) in the glia when it crosses the blood–brain barrier.…”

Inhibition of transcription factor SP1 produces neuroprotective effects through decreasing MAO B activity in MPTP/MPP+ Parkinson's disease models

“…However, previous research showed contradictory data obtained in PD patients in whom the MAO B level in the striatum remained unchanged and remained at the control level (Gargalidis‐Moudanos, Pizzinat, Javoy‐Agid, Remaury, & Parini, ). Conversely, in the striatum of asymptomatic and early symptomatic stages of PD mouse models, MAO B expression and activity showed compensatory decreases due to the comprehensive assessment of the molecular mechanisms of neuroplasticity in MPTP models of preclinical and clinical stages of PD (Mingazov et al, ). The difference or contradiction in changes in MAO B levels in the parkinsonian striatum in the present and the above studies suggest that observed time points and the PD clinical stage might influence the MAO B levels in the parkinsonian striatum, and this possibility requires further investigation.…”

Parkinson’s Disease-Induced Zebrafish Models: Focussing on Oxidative Stress Implications and Sleep Processes

“…Thus, Kirchhoff et al [ 94 ] reported that two MPTP injections (15 or 20 mg/kg) for 7 consecutive days were sufficient to cause dopaminergic neuron loss in mice. Thus, in a recent report of Mingazov et al [ 95 ], it was demonstrated that 12 mg/kg b.w./day subcutaneous MPTP treatment for 2 weeks could not induce DA metabolism impairment or MAO-A and MAO-B enzyme activity changes even with DA neuron loss confirmation.…”