Dataset Information

Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism.

ABSTRACT: Background Dopamine (DA) neuron-selective uptake and toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans. Loss of DA neurons via mitochondrial damage and oxidative stress is reproduced by systemic injection of MPTP in animals, which serves as models of parkinsonism and Parkinson's disease (PD). This study aimed to test whether pan-neural supplementation of the longevity-related, pleiotropic deacetylase SIRT1, which confers partial tolerance to at least three models of stroke and neurodegeneration, could also alleviate MPTP-induced acute pathological changes in nigrostriatal DA neurons and neighboring glia. Results We employed a line of prion promoter-driven Sirt1-transgenic (Sirt1Tg) mice that chronically overexpress murine SIRT1 in the brain and spinal cord. Sirt1Tg and wild-type (WT) male littermates (3?4 months old) were subjected to intraperitoneal injection of MPTP. Acute histopathological changes in the midbrain and striatum (caudoputamen) were assessed with serial coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA. In the substantia nigra pars compacta (SNpc) of the midbrain, the number of TH-positive neurons and the reactive gliosis were comparable between the Sirt1Tg and WT littermates. In the striatum, the relative fluorescence intensity of TH-positive nerve terminals and the level of gliosis did not differ by the genotypes. Conclusions Sirt1Tg and WT littermate mice exhibited comparable acute histopathological reactions to the systemic injection of MPTP, loss of TH-positive neurons and reactive gliosis. Thus, the genetic supplementation of SIRT1 does not confer histologically recognizable protection on nigrostriatal DA neurons against acute toxicity of MPTP.

SUBMITTER: Kitao Y

PROVIDER: S-EPMC4482211 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism.

Kitao Yasuko Y Ageta-Ishihara Natsumi N Takahashi Ryosuke R Kinoshita Makoto M Hori Osamu O

F1000Research 20150527

Background Dopamine (DA) neuron-selective uptake and toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans. Loss of DA neurons via mitochondrial damage and oxidative stress is reproduced by systemic injection of MPTP in animals, which serves as models of parkinsonism and Parkinson's disease (PD). This study aimed to test whether pan-neural supplementation of the longevity-related, pleiotropic deacetylase SIRT1, which confers partial tolerance to at least t ...[more]

PMID: 26167274

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Project description:Presence of parkinsonian features after carbon monoxide (CO) intoxication is well known and the severity was found to relate to the pre-synaptic dopaminergic deficits. There is no systemic study to analyse the functional network involved in CO-related Parkinsonism. Forty-five CO-related parkinsonism patients and 25 aged-matched controls completed the 3D T1-weighted imaging and (18)F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET). Voxel-based morphometry (VBM) was performed to assess the structural and functional brain differences between the patients and controls. Spatial covariant networks responsible for distinguishing patients and controls were constructed using independent component analysis. For validation, the pre-synaptic dopaminergic functional network was established by regression model using striatal TRODAT-1 SPECT as the independent variable. The clinical significance of both networks was determined by correlation with the Unified Parkinson's Disease Rating Scale (UPDRS). Compared with controls, the spatial covariant signals of FDG-PET were significantly lower in the medial and lateral frontal, caudate nucleus, dorsomedial prefrontal areas, and temporal-parietal regions while the spatial intensities correlated significantly with UPDRS total scores. The functional network that correlated with striatum pre-synaptic dopaminergic uptakes included the midbrain, thalamus, caudate, lateral frontal cortex, ventral striatum, ventral, or dorsal anterior cingulate cortex. Both networks overlapped considerably and the topographies reflected structural damage pattern. Our study provides evidence that glucose metabolism in CO-parkinsonism patients pertains to an organized covariant pattern in the cortical regions that is spatially coherent with the cortical map of pre-synaptic dopamine deficits. As the fronto-temporal, striatum, and temporal-parietal areas were involved, the unique metabolic covariant network suggests a different pathophysiology in CO-related parkinsonism.

Dataset Information

Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism.

Publications

Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism.

Similar Datasets

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