Behavior, neurotransmitters and inflammation in three regimens of the MPTP mouse model of Parkinson's disease.
ABSTRACT Three common dosing regimens of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of Parkinson's disease (PD) were compared in C57BL/6 mice on behavior, striatal and extra-striatal neurotransmission, and brain cytokines, to clarify the differences between regimens on these variables. Acute regimen: Rotorod performance and open field grooming were decreased. Striatal dopamine (DA) was depleted, but DA turnover increased. Striatal noradrenalin (NA), frontal cortex serotonin (5-HT) and midbrain NA and DA were all depleted. Sub-acute regimen: Opposite to the acute regimen, rotorod and pole test performance, and open field grooming were all increased. Striatal DA was depleted, but DA turnover was increased more than in the acute regimen. Striatal 5-HT turnover and cortical NA were increased as well. Chronic regimen: Rotorod performance was impaired, but open field distance moved increased. Striatal DA was severely depleted and DA and 5-HT turnover strongly increased. Striatal 5-HT, frontal cortex NA and DA, and cortical DA were all depleted. Pro-inflammatory cytokines interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-10 were only increased in the chronic regimen, but these cytokines were found to be similarly related to striatal DA turnover in all regimens. The study demonstrated that the presence of behavioral differences between regimens may depend on the type of behavioral tests used and the extent to which dopaminergic, non-dopaminergic and extra-striatal neurotransmission are affected in the regimens. The study also provided additional evidence for the validity of the relatively new chronic MPTP/probenecid model. In all, the results suggested that dosing regimens should be carefully pre-considered.
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ABSTRACT: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinson's disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5 months were followed up to a maximum age of 21 months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post-MPTP intoxication decrease in dopamine cell was no longer significant at 21 months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14 months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In bothgroups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process.Journal of Neurochemistry 06/2012; 122(5):1032-46. · 3.97 Impact Factor
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ABSTRACT: Changes in cannabinoid receptor expression and concentration of endocannabinoids have been described in Parkinson's disease; however, it remains unclear whether they contribute to, or result from, the disease process. To evaluate whether targeting the endocannabinoid system could provide potential benefits in the treatment of the disease, the effect of a monoacylglycerol lipase inhibitor that prevents degradation of 2-arachidonyl-glycerol was tested in mice treated chronically with probenecid and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPp). Chronic administration of the compound, JZL184 (8 mg/kg), prevented MPTPp-induced motor impairment and preserved the nigrostriatal pathway. Furthermore, none of the hypokinetic effects associated with cannabinoid receptor agonism were observed. In the striatum and substantia nigra pars compacta, MPTPp animals treated with JZL184 exhibited astroglial and microglial phenotypic changes that were accompanied by increases in TGFβ messenger RNA expression and in glial cell-derived neurotrophic factor messenger RNA and protein levels. JZL184 induced an increase in β-catenin translocation to the nucleus, implicating the Wnt/catenin pathway. Together, these results demonstrate a potent neuroprotective effect of JZL184 on the nigrostriatal pathway of parkinsonian animals, likely involving restorative astroglia and microglia activation and the release of neuroprotective and antiinflammatory molecules.Neurobiology of aging. 05/2014;
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ABSTRACT: The accumulation of misfolded a-synuclein is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other alpha-synucleinopathies. However, how alpha-synuclein causes neurodegeneration is unresolved. Several studies have supported the involvement of dynein, the major motor for retrograde axonal transport in alpha-synuclein-dependent neurodegeneration, especially in the nigrostriatal system. Therefore, we examined the nigrostriatal dyneins in transgenic mice that overexpress human A53T alpha-synuclein and recapitulate key features of a PD-like neuronal synucleinopathy. Age-matched nontransgenic littermates were used as controls. The results demonstrated that the protein level of dynein was decreased in the striatum, whereas it was elevated in the substantia nigra. Double immunostaining results revealed that the reduction in dynein level was associated with aggregation of A53T a-synuclein in the striatum. Furthermore, we performed a quantitative analysis of motor behaviors in A53T alpha-synuclein transgenic mice and controls using a modified open field test. We demonstrated that the protein level of dynein in the striatum was significantly correlated with the motor behaviors. Together, our data indicate that dynein changes in the nigrostriatal system of A53T alpha-synuclein transgenic mice may contribute to their severe movement disorder.F1000Research. 01/2014; 3:68.