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Published on: January 7, 2014
Systemic administration of proteasome inhibitor protects against MPTP neurotoxicity in mice
Takuya Oshikawa1, Hayato Kuroiwa, Ryohei Yano
1Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78, Sho-machi, Tokushima, 770-8505, Japan.
Abstract:
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.
Insights
Proteasome inhibitors like PSI protect against MPTP-induced neurotoxicity in mice by preserving dopamine levels and preventing neuron loss. This suggests a potential therapeutic strategy for Parkinson's disease pathogenesis.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Proteasome dysfunction is implicated in the degeneration of nigrostriatal dopaminergic neurons.
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin used to model Parkinson's disease.
- Dopaminergic neuron loss is a hallmark of Parkinson's disease.
Purpose of the Study:
- To investigate the neuroprotective effects of proteasome inhibitor PSI against MPTP-induced neurotoxicity in mice.
- To determine if PSI administration can prevent the loss of dopaminergic neurons and associated neurochemical changes.
- To explore the role of ubiquitination in the neuroprotective mechanism of PSI.
Main Methods:
- Mice were treated with MPTP to induce neurotoxicity.
- Carbobenzoxy-L-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI) was administered at different doses.
- Neurochemical analysis (dopamine, DOPAC, HVA), Western blot (TH, GFAP), and immunohistochemistry (TH, ubiquitin) were performed.
Main Results:
- MPTP treatment significantly reduced striatal dopamine, DOPAC, and HVA levels.
- PSI administration (0.3 and 1.0 mg/kg) prevented these MPTP-induced decreases.
- PSI (1.0 mg/kg) prevented TH protein loss, GFAP increase, and TH-positive neuron loss, while increasing ubiquitin-positive cells.
Conclusions:
- Proteasome inhibitors, specifically PSI, demonstrate neuroprotective effects against MPTP neurotoxicity in mice.
- The neuroprotective mechanism may involve the elevation of ubiquitination, counteracting dopaminergic cell damage.
- These findings offer valuable insights into Parkinson's disease pathogenesis and potential therapeutic interventions.
