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: 2.98). 06/2009; 98(1-2):130-8. DOI: 10.1016/j.physbeh.2009.04.021
Source: PubMed


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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    • "The cages of some mice treated with MPTPp were placed on a heating pad on injection days at the recommendation of the NCTR veterinarians who suggested this procedure if the mouse appeared cold and/or was moving slowly or somewhat immobile. Similar procedures (e.g., increased temperature of the housing room) have been used by others to prevent MPTP-induced hyperthermia [29] [30]. The seven mice in the control group were ip (first injection) and subcutaneously (second injection) injected with saline on PND 45–76 (n = 3) or PND 52–83 (n = 4) at the same times as the MPTPp group to control for potential injection effects. "
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    ABSTRACT: The chronic MPTP+probenecid treatment paradigm has been used to successfully model the neurochemical, neuropathological, and behavioral effects associated with Parkinson's disease. Here, adult male C57Bl/6 mice were injected ip with 25mg/kg MPTP and 250mg/kg probenecid (MPTPp) or saline twice weekly for a total of 10 injections. Behavioral assessments included motor coordination, grip strength, spatial learning/memory, locomotor activity, and anhedonia. Those assessments were repeated up to 8 weeks post-treatment. In a subsequent experiment, adult male mice were treated with saline or MPTPp as described above. One-half of each group was allowed access to 1% trehalose in the water bottle. Trehalose intake averaged 1.90-2.34g/kg. Behavioral assessments included locomotor activity, olfaction, motor coordination, grip strength, and exploratory behavior. Those assessments were repeated 4 weeks post-treatment. The strongest MPTPp effect was hyperactivity as exhibited in the open field. This increased activity was apparent in both experiments and occurred at all time points post-treatment. Assessments of grip strength, water maze performance, olfaction, and exploratory behavior did not indicate MPTPp-related alterations. When the specifications for the motor coordination test were made somewhat easier in the second experiment, there were deficits exhibited by the MPTPp group, the MPTPp+trehalose group and the trehalose group. The addition of trehalose did not alleviate any of the MPTPp-induced behavioral alterations; however, trehalose treatment significantly attenuated the striatal decreases in DA, DOPAC, HVA and 5-HIAA. These results provide a more comprehensive description of the behavioral alterations resulting from the chronic MPTPp treatment regimen and suggest that trehalose at this concentration does not act as a complete neuroprotectant. Published by Elsevier B.V.
    Behavioural brain research 06/2015; 292:68-78. DOI:10.1016/j.bbr.2015.05.057 · 3.03 Impact Factor
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    • "TNF-α, IL-1β and IL-10 were measured in the hippocampus as previously described [31]. In brief, a customized 3-plex rat cytokine panel consisting of fluorescent beads for IL-1β, TNF-α and IL-10 (BioRad, CA, USA) was analyzed with a Luminex protein suspension array system (Bioplex 200, Biorad, CA, USA) according to manufacturer’s instructions. "
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    ABSTRACT: Background In Alzheimer’s disease, stroke and brain injuries, activated microglia can release proinflammatory cytokines, such as interleukin (IL)-1β. These cytokines may change astrocyte and neurotrophin functions, which influences neuronal survival and induces apoptosis. However, the interaction between neuroinflammation and neurotrophin functions in different brain conditions is unknown. The present study hypothesized that acute and subacute elevated IL-1β differentially modulates glial and neurotrophin functions, which are related to their role in neuroprotection and neurodegeneration. Method Rats were i.c.v. injected with saline or IL-1β for 1 or 8 days and tested in a radial maze. mRNA and protein expressions of glial cell markers, neurotrophins, neurotrophin receptors, β-amyloid precursor protein (APP) and the concentrations of pro- and anti-inflammatory cytokines were measured in the hippocampus. Results When compared to controls, memory deficits were found 4 days after IL-1 administrations, however the deficits were attenuated by IL-1 receptor antagonist (RA). Subacute IL-1 administrations increased expressions of APP, microglial active marker CD11b, and p75 neurotrophin receptor, and the concentration of tumor necrosis factor (TNF)-α and IL-1β, but decreased expressions of astrocyte active marker glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and TrK B. By contrast, up-regulations of NGF, BDNF and TrK B expressions were found after acute IL-1 administration, which are associated with the increase in both glial marker expressions and IL-10 concentrations. However, TrK A was down-regulated by acute and up-regulated by subacute IL-1 administrations. Subacute IL-1-induced changes in the glial activities, cytokine concentrations and expressions of BDNF and p75 were reversed by IL-1RA treatment. Conclusion These results indicate that acute and subacute IL-1 administrations induce different changes toward neuroprotection after acute IL-1 administrations but neurodegeneration after subacute ones.
    Journal of Neuroinflammation 05/2013; 10(1):59. DOI:10.1186/1742-2094-10-59 · 5.41 Impact Factor
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    • "This is a known limitation of rodent MPTP models of PD, probably because DA cell loss and accompanying striatal DA depletion is insufficient to induce a behavioural phenotype. Others have reported deficits in the grid test and the open field test in MPTP/probenecid-treated mice [15][33] but levels of striatal DA depletion achieved in these studies were far greater than those reported here. Of interest, however, both apamin and bee venom stimulated the locomotor activity in mice intoxicated with MPTP/probenecid, indicating that in this experimental situation, both treatments probably had the capacity to stimulate DA release [36], possibly by a mechanism involving SK channel blockade. "
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    ABSTRACT: Bee venom has recently been suggested to possess beneficial effects in the treatment of Parkinson disease (PD). For instance, it has been observed that bilateral acupoint stimulation of lower hind limbs with bee venom was protective in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In particular, a specific component of bee venom, apamin, has previously been shown to have protective effects on dopaminergic neurons in vitro. However, no information regarding a potential protective action of apamin in animal models of PD is available to date. The specific goals of the present study were to (i) establish that the protective effect of bee venom for dopaminergic neurons is not restricted to acupoint stimulation, but can also be observed using a more conventional mode of administration and to (ii) demonstrate that apamin can mimic the protective effects of a bee venom treatment on dopaminergic neurons. Using the chronic mouse model of MPTP/probenecid, we show that bee venom provides sustained protection in an animal model that mimics the chronic degenerative process of PD. Apamin, however, reproduced these protective effects only partially, suggesting that other components of bee venom enhance the protective action of the peptide.
    PLoS ONE 04/2013; 8(4):e61700. DOI:10.1371/journal.pone.0061700 · 3.23 Impact Factor
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