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.
Highlights
Dopamine (DA) transporter-mediated uptake of 1-methyl-4-phenylpyridine (MPP+), an oxidized metabolite of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), damage DA neurons by impairing mitochondrial respiratory chain and generating reactive oxygen species[1]
The expression levels of SIRT1 in the midbrain and striatum assessed by immunoblot were approximately three times higher in heterozygous Tg mice than in the non-Tg (WT) littermates[12]
The numbers of tyrosine hydroxylase (TH)-positive neuronal somata in the substantia nigra pars compacta (SNpc) did not show statistically significant difference (Figure 1B). These data indicate that the supplementation of SIRT1 does not suppress the loss of DA neurons and reactive gliosis by acute MPTP toxicity
Summary
Dopamine (DA) transporter-mediated uptake of 1-methyl-4-phenylpyridine (MPP+), an oxidized metabolite of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), damage DA neurons by impairing mitochondrial respiratory chain and generating reactive oxygen species[1]. The DA neuron-selective toxicity is reproduced in animals by systemic administration of MPTP, which serve as models of Parkinson’s disease (PD)[2]. Dopamine (DA) neuron-selective uptake and toxicity of 1-methyl-4phenyl-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 alleviate MPTP-induced acute pathological changes in nigrostriatal DA neurons and neighboring glia
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