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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 Y, Ageta-Ishihara N, Takahashi R, Kinoshita M, Hori O - F1000Res (2015)

Bottom Line: 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.Thus, the genetic supplementation of SIRT1 does not confer histologically recognizable protection on nigrostriatal DA neurons against acute toxicity of MPTP.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroanatomy, Kanazawa University, Takara-machi, Kanazawa, 920-8640, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

SIRT1 overexpression does not alleviate MPTP-induced loss of striatal DA nerve terminals and astrogliosis.(A) Representative immunofluorescence images of wild-type and Sirt1Tg mouse striatum/caudoputamen 4 days after intraperitoneal injection of saline with or without MPTP. Coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA (DAPI) exhibited no recognizable histopathological differences in the loss of TH-positive cells (presumed axons and axon terminals of DA neurons) and in the proliferation of GFAP-positive astrocytes. Scale bars, 100 μm. (B) The relative immunofluorescence intensity for TH in the striatum was comparable between WT and Tg littermates. The bars denote mean ± standard error of the mean (n = 4 × 4).
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f2: SIRT1 overexpression does not alleviate MPTP-induced loss of striatal DA nerve terminals and astrogliosis.(A) Representative immunofluorescence images of wild-type and Sirt1Tg mouse striatum/caudoputamen 4 days after intraperitoneal injection of saline with or without MPTP. Coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA (DAPI) exhibited no recognizable histopathological differences in the loss of TH-positive cells (presumed axons and axon terminals of DA neurons) and in the proliferation of GFAP-positive astrocytes. Scale bars, 100 μm. (B) The relative immunofluorescence intensity for TH in the striatum was comparable between WT and Tg littermates. The bars denote mean ± standard error of the mean (n = 4 × 4).

Mentions: In the striatum/caudoputamen without MPTP administration, the staining patterns for TH (mostly axons and axon terminals of DA neurons), GFAP-positive astrocytes, and the nuclei of these and other cells were comparable between the Tg and WT littermates (Figure 2A, left). Loss of TH-positive neuropil and reactive gliosis after MPTP administration were also comparable between the genotypes (Figure 2A, middle; higher magnifications in the right). Fluorescence intensity for TH in the striatum after MPTP administration did not differ (Figure 2B), indicating that the supplementation of SIRT1 does not alleviate the loss of DA nerve terminals by acute MPTP toxicity.


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

Kitao Y, Ageta-Ishihara N, Takahashi R, Kinoshita M, Hori O - F1000Res (2015)

SIRT1 overexpression does not alleviate MPTP-induced loss of striatal DA nerve terminals and astrogliosis.(A) Representative immunofluorescence images of wild-type and Sirt1Tg mouse striatum/caudoputamen 4 days after intraperitoneal injection of saline with or without MPTP. Coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA (DAPI) exhibited no recognizable histopathological differences in the loss of TH-positive cells (presumed axons and axon terminals of DA neurons) and in the proliferation of GFAP-positive astrocytes. Scale bars, 100 μm. (B) The relative immunofluorescence intensity for TH in the striatum was comparable between WT and Tg littermates. The bars denote mean ± standard error of the mean (n = 4 × 4).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4482211&req=5

f2: SIRT1 overexpression does not alleviate MPTP-induced loss of striatal DA nerve terminals and astrogliosis.(A) Representative immunofluorescence images of wild-type and Sirt1Tg mouse striatum/caudoputamen 4 days after intraperitoneal injection of saline with or without MPTP. Coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA (DAPI) exhibited no recognizable histopathological differences in the loss of TH-positive cells (presumed axons and axon terminals of DA neurons) and in the proliferation of GFAP-positive astrocytes. Scale bars, 100 μm. (B) The relative immunofluorescence intensity for TH in the striatum was comparable between WT and Tg littermates. The bars denote mean ± standard error of the mean (n = 4 × 4).
Mentions: In the striatum/caudoputamen without MPTP administration, the staining patterns for TH (mostly axons and axon terminals of DA neurons), GFAP-positive astrocytes, and the nuclei of these and other cells were comparable between the Tg and WT littermates (Figure 2A, left). Loss of TH-positive neuropil and reactive gliosis after MPTP administration were also comparable between the genotypes (Figure 2A, middle; higher magnifications in the right). Fluorescence intensity for TH in the striatum after MPTP administration did not differ (Figure 2B), indicating that the supplementation of SIRT1 does not alleviate the loss of DA nerve terminals by acute MPTP toxicity.

Bottom Line: 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.Thus, the genetic supplementation of SIRT1 does not confer histologically recognizable protection on nigrostriatal DA neurons against acute toxicity of MPTP.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroanatomy, Kanazawa University, Takara-machi, Kanazawa, 920-8640, Japan.

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.

No MeSH data available.


Related in: MedlinePlus