Progressive Dopaminergic Degeneration in the Chronic MPTPp Mouse Model of Parkinson’s Disease

Abstract

Parkinson's disease (PD) is characterized by a progressive degeneration of dopamine (DA) neurons and gradual worsening of motor symptoms. The investigation of progressive degenerative mechanisms and potential neuroprotective strategies relies on experimental models of the chronic neuropathology observed in human. The present study investigated the progressive nature of neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp) chronic mouse model of PD. MPTP (25 mg/kg) plus probenecid (250 mg/kg) were administered twice a week for 5 weeks. We evaluated behavioral deficits (olfactory and motor impairment), neurodegeneration (loss of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, SNc), biochemical markers of functional impairment in the caudate-putamen (CPu) (striatal enkephalin mRNA, DA and DOPAC levels), and glial reactivity (CD11b and GFAP immunoreactivity in the SNc and CPu) at progressive time-points (after 1, 3, 7, and 10 administrations of MPTPp). Olfactory dysfunction already appeared after the 1st MPTPp injection, whereas motor dysfunction appeared after the 3rd and worsened upon subsequent administrations. Moreover, starting after three MPTPp injections, we observed a gradual decline of TH-positive cells in the SNc, and a gradual raise of enkephalin mRNA in the CPu. Striatal DA levels reduction was not different among all time-points evaluated, whereas DOPAC levels were similarly reduced after 1-7 MPTP injections, but were further decreased after the 10th injection. Reactive microglia and astroglia were observed in both the SNc and CPu from the 1st MPTPp administration. In the SNc, gliosis displayed a gradual increase over the treatment. After 2 months, TH, DA, DOPAC, and reactive glia in the SNc were still altered in MPTPp-treated mice as compared to controls. By showing a progressive development of behavioral deficits and nigral neurodegeneration, together with impairment of biochemical parameters and gradual increase of glial response, results suggest that the chronic MPTPp protocol is a model of progressive PD, which may be suitable to investigate chronic pathological processes and neuroprotective strategies in PD.

Interleukin-22 protects rat PC12 pheochromocytoma cells from serum deprivation-induced cell death

“…Both neurotoxins caused a significant loss of nigral tyrosine hydroxylase-immunostained cells and striatal dopamine depletion, but 6-OHDA caused more widespread and intense cell loss, more intense body weight loss, and more mortality than MPTP [29,30]. The main advantage of the MPTP was that MPTP-lesioned rats are a good model of early phase PD because these animals presented less loss of body weight, resulting in lower animal suffering, morbidity, and mortality compared to the 6-OHDA rat model [29,31]. MPP ?…”

Profiling changes in gait dynamics resulting from progressive 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced nigrostriatal lesioning

“…One of the harrowing challenges of characterizing and developing therapeutics for Parkinson's disease is consistently reproducing a nonhuman animal model. Some of the most successful representations are chronic or progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion models, which produce long-lasting neurodegeneration in the nigrostriatal pathway (Bezard et al, 1997(Bezard et al, , 2001Meredith et al, 2002;Schintu et al, 2009). The current weakness in these models is not in reproducing the pathologies but in correlating them with a consistent behavioral deficit profile that accurately reflects motordependent behaviors.…”

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

“…These features were also evident in our model. However, it should be noted that MPTP shows affinity, although much lower, for DAT located on other cell groups as well as other monoamine receptors (228, 383) potentially inducing non-specific cell death, particularly in acute models (228,384). As the sections for immunogold quantifications of AQP4 are only labeled with this antibody, we cannot rule out that unspecific cell loss has occurred in our model and that AQP4 is upregulated around these cells and included in our analysis.…”

“…This striatal region corresponds to our site of injection and may thus induce cell death in these neurons through DAT and/or AQP9, potentially reflecting a PD-specific pattern. Alternatively, it may reflect a side effect of the acute model, which may induce more unspecific cell loss compared to chronic models (228,363,384). In regard to the age-related differences between the models, it should be noted that the animals included in the HPLC analysis range from 5-10 months, which may potentially influence our results.…”