Systemic Administration of Proteasome Inhibitor Protects Against MPTP Neurotoxicity in Mice
| Autor: | Hayato Kuroiwa, Naoto Kadoguchi, Ryohei Yano, Takuya Oshikawa, Hironori Yokoyama, Hiroyuki Kato, Tsutomu Araki |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Tyrosine 3-Monooxygenase Dopamine Blotting Western Lactacystin Substantia nigra Striatum Pharmacology Biology Mice Cellular and Molecular Neuroscience chemistry.chemical_compound Glial Fibrillary Acidic Protein medicine Animals Enzyme Inhibitors Chromatography High Pressure Liquid Neurons Tyrosine hydroxylase Ubiquitin MPTP Neurotoxicity Cell Biology General Medicine medicine.disease Immunohistochemistry Mice Inbred C57BL Neostriatum Substantia Nigra nervous system chemistry Biochemistry 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine Proteasome inhibitor Proteasome Inhibitors medicine.drug |
| Zdroj: | Cellular and Molecular Neurobiology. 29:769-777 |
| ISSN: | 1573-6830 0272-4340 |
| Popis: | Dysfunction of the proteasome has been suggested to contribute in the degeneration of nigrostriatal dopaminergic neurons. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L: -gamma-t-butyl-L: -glutamyl-L: -alanyl-L: -leucinal (PSI) protects against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice. Three administrations of MPTP at 1-h intervals to mice reduced significantly the concentration of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) in the striatum after 5 days. In contrast, PSI (0.3 and 1.0 mg/kg) prevented a significant decrease in dopamine, DOPAC and HVA contents of the striatum 5 days after MPTP treatment. In our Western blot analysis study, PSI at a dose of 1.0 mg/kg prevented a significant decrease in TH (tyrosine hydroxylase) protein and a significant increase in glial fibrillary acidic protein 5 days after MPTP treatment. Furthermore, our immunohistochemical study showed that PSI at a dose of 1.0 mg/kg prevented a significant loss in TH immunopositive neurons in the striatum and substantia nigra 5 days after MPTP treatment. In contrast, PSI caused a significant increase in the number of intense ubiquitin immunopositive cells in the striatum and substantia nigra 5 days after MPTP treatment. These results indicate that proteasome inhibitors can protect against MPTP neurotoxicity in mice. The neuroprotective effect of PSI against dopaminergic cell damage may be mediated by the elevation of ubiquitination. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease. |
| Databáze: | OpenAIRE |
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