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: It has been suggested that DNA vaccine plays a protective effect on degenerative diseases in the central nervous system (CNS), the Parkinson's disease (PD) included. In this study, we assessed the immune effects of optimized DNA vaccine (pVAX1-IL-4/SYN-B) in the C57BL/6 mice by ELISA, and immunohistochemistry. We also evaluated the neuroprotective effect of pVAX1-IL-4/SYN-B in MPTP model of Parkinson's disease, using behavioral methods, immunohistochemistry and western blot. We found that alphα-synuclein (α-syn) antibody significantly increased, IL-4 increased and IFN-r reduced in the serum of immunized C57BL/6 mice in optimized DNA vaccine group. The immune serum of mice specifically combined with the α-syn positive inclusion bodies in the brain of PD model mice. The preventive immunization with optimized DNA vaccine made the motor symptoms improved significantly, the apoptosis of tyrosine hydroxylase (TH) neuron and cyclooxygenase-2 (COX-2) expression significantly decreased in MPTP model mice. These results suggest that optimized DNA vaccine can make immunized mice produce high titers of specific α-syn antibody, mainly causing the humoral immune response; preventive immunization with optimized DNA vaccine can play neuroprotective and anti-inflammatory effects on mice suffering from the sub-acute MPTP Parkinson's disease.Neurological Sciences 01/2013; · 1.41 Impact Factor
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ABSTRACT: BACKGROUND: In Alzheimer's disease, stroke and brain injuries, activated microglia can release proinflammatory cytokines, such as interleukin (IL)-1beta. 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-1beta 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-1beta for 1 or 8 days and tested in a radial maze. mRNA and protein expressions of glial cell markers, neurotrophins, neurotrophin receptors, beta-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)-alpha and IL-1beta, 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. · 4.35 Impact Factor
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ABSTRACT: Telmisartan (TEL), an angiotensin type 1 receptor (AT1R) antagonist, has been reported to exert neuroprotective effect in animal models of Parkinson's disease (PD). However, its effect on motor functions, mutant protein α-synuclein (SYN) and neurotrophic factors (BDNF and GDNF) expression and their interrelation in PD has not yet been elucidated. In the present study, the effect of TEL on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced motor dysfunctions and dopaminergic degeneration was ascertained through investigating the alterations in protein expression of dopamine transporter (DAT), tyrosine hydroxylase (TH) and SYN in C57BL/6J mouse. Further, the role of TEL on the gene expression of neurotrophic factors such as BDNF and GDNF and protein expression of vesicular monoamine transporter 2 (VMAT2) and Glial fibrillary acidic proteins (GFAP) were studied. In TEL treated mouse, strong negative correlation was observed between motor function and SYN, while a strong positive correlation was noted with BDNF and GDNF expression. TEL caused down-regulation of SYN, GFAP and up-regulation of DAT, TH, VAMT2, BDNF and GDNF expressions. Present data suggest that brain renin angiotensin system (RAS) plays a crucial role in motor function and in the regulation of key proteins such as SYN, BDNF and GDNF, DAT, TH, VMAT2 and GFAP in Parkinsonism. In conclusion, the present study shows that angiotensin type 1 receptor antagonists can ameliorate motor dysfunction and act as potential neuroprotective agent in the management of Parkinsonism.Neuropharmacology 06/2013; · 4.11 Impact Factor