Behavior, neurotransmitters and inflammation in three regimens of the MPTP mouse model of Parkinson’s disease

Department of Biomedical Sciences, AVC, University of Prince Edward Island, and NRC Institute for Nutriscience and Health, Charlottetown, PE, Canada C1A 5T1.
Physiology & Behavior (Impact Factor: 3.03). 06/2009; 98(1-2):130-8. DOI: 10.1016/j.physbeh.2009.04.021
Source: PubMed

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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    • "sion and motor behavior is further supported by the study of the MPTP - intoxicated mice . Indeed , in intoxicated mice 10 days after intoxication , the only change in motor behavior was a spontaneous hyperactivity . Deficits in motor behavior have frequently been reported in MPTP - intoxicated mice ( Sedelis et al . 2001 ; Meredith et al . 2008 ; Luchtmann et al . 2009 ) , but only when the evaluations were performed 1 – 5 days after intoxication . After 1 week , this acute motor deficit was reported to be attenuated and a spontaneous hyperactivity was observed even after chronic MPTP intoxication ( Rouss - elet et al . 2003 ; Meredith and Kang 2006 ) . The late spontaneous hyperactivity observed in c"
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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. DOI:10.1111/j.1471-4159.2012.07837.x · 4.24 Impact Factor
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    • "To assess complex behavioral phenotypes of mouse models of neurodegenerative diseases, diverse types of behavioral assays have been applied: for example, Morris water maze and Y-maze tests have been used to assess learning and memory in Alzheimer disease (AD) models, RotaRod test to assess motor coordination in Parkinson's (PD) and Huntington's disease (HD) models, and openfield test to assess the locomotor activity of PD, HD and AD models [4] [5] [6] [7] [8] [9] [10]. While these specialized tests are well suited to quantifying certain motor or memory deficits, each gives only a partial view of the behavioral phenotype, and many have other limitations: a requirement that the investigator be present at the time measurements are taken, which influences mouse behavior; an assessment of induced artificial behaviors, rather than natural, routine behaviors ; a restriction to short time periods, ranging from minutes to at most a few hours; and a low-throughput, which can be problematic for large-scale therapeutic screening [1] [2]. "
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    ABSTRACT: Changes in routine mouse home-cage behavioral activities have been used recently to study alterations of neural circuits caused by genetic and environmental modifications and by drug administration. Nevertheless, automatic assessment of mouse home-cage behaviors remains challenging due to the cost of proprietary systems and to the difficulty in adjusting systems to different monitoring conditions. Here we present software for the automatic quantification of multiple facets of mouse home-cage behaviors, suitable for continuous 24 h video monitoring. We used this program to assess behavioral changes in male and female R6/2 transgenic mouse models of Huntington's disease over a 10-week period. Consistent with the well-known progressive motor coordination deficits of R6/2 mice, their hanging, rearing, and climbing activity declined as the disease progressed. R6/2 mice also exhibited frequent disturbances in their resting activity compared to wild-type mice, suggesting that R6/2 mice are more restless and wakeful. Behavioral differences were seen earlier for male R6/2 mice than female R6/2 mice, and "behavioral signatures" based on multiple behaviors enabled us to distinguish male R6/2 mice from sex- and age-matched wild-type controls as early as 5 weeks of age. These results demonstrate that the automated behavioral classification software that we developed ("OpenCage") provides a powerful tool for analyzing natural home-cage mouse behaviors, and for constructing behavioral signatures that will be useful for assessing therapeutic strategies. The OpenCage software is available under an open-source GNU General Public License, allowing other users to freely modify and extend it to suit their purposes.
    Behavioural brain research 04/2012; 229(1):216-25. DOI:10.1016/j.bbr.2012.01.015 · 3.39 Impact Factor
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    • "This is the first study to investigate the effects of E-EPA in an in vivo PD model, as all other studies used fish oil (containing both EPA and DHA). Our initial findings were encouraging, as E-EPA prevented hypokinesia, hyperactivity and a procedural memory deficit in the water maze, and loss of body weight induced by MPTP-P, one of the most severe and valid regimens of the MPTP model [27] "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder, characterized by hypokinesia, but also mood and cognitive disorders. Neuropathologically, PD involves loss of nigrostriatal dopamine (DA) and secondary non-dopaminergic abnormalities. Inflammation may contribute to PD pathogenesis, evident by increased production of pro-inflammatory cytokines. PD onset has been positively associated with dietary intake of omega-(n)-6 polyunsaturated fatty acids (PUFA). On the other hand, omega-(n)-3 PUFA may benefit PD. One of these n-3 PUFA, eicosapentaenoic acid (EPA), is a neuroprotective lipid with anti-inflammatory properties, but its neuroprotective effects in PD are unknown. Thus, we presently tested the hypothesis that EPA can protect against behavioral impairments, neurodegeneration and inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-probenecid (MPTP-P) mouse model of PD. MPTP-P injections caused hypokinesia in the rotorod and pole test, hyperactivity in the open field, and impaired mice on the cued version (procedural memory) of the Morris water maze. MPTP-P caused a loss of nigrostriatal DA and altered neurochemistry in the frontal cortex and hippocampus. Furthermore, striatal levels of pro-inflammatory cytokines were increased, while the brain n-3/n-6 lipid profile remained unaltered. Feeding mice a 0.8% ethyl-eicosapentaenoate (E-EPA) diet prior to MPTP-P injections increased brain EPA and docosapentaenoic acid (DPA) but not docosahexaenoic acid (DHA) or n-6 PUFA. The diet attenuated the hypokinesia induced by MPTP-P and ameliorated the procedural memory deficit. E-EPA also suppressed the production of pro-inflammatory cytokines. However, E-EPA did not prevent nigrostriatal DA loss. Based on this partial protective effect of E-EPA, further testing may be warranted.
    Behavioural brain research 01/2012; 226(2):386-96. DOI:10.1016/j.bbr.2011.09.033 · 3.39 Impact Factor
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