Proteasome Inhibitor Does Not Enhance MPTP Neurotoxicity in Mice

Kadoguchi, Naoto; Umeda, Masahiro; Kato, Harubumi; Araki, Tsutomu

doi:10.1007/s10571-008-9271-4

Cited by 11 publications

(7 citation statements)

References 40 publications

(43 reference statements)

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“…In contrast, conventional MPTP injection induces only a brief UPS inhibition (<24 h) and fails to produce protein aggregation (Fornai et al 2005). Interestingly, under conditions of conventional MPTP administration, the reversible UPS inhibitor PSI either does not enhance neurodegeneration (Kadoguchi et al 2008), or even protects dopaminergic neurons against the MPTP-induced toxicity in mice (Oshikawa et al 2009), thus confirming the earlier observation from in vitro models that the severity and duration of the UPS inhibition may determinate the final, beneficial or adverse effect of the UPS inhibitors.…”

Section: Discussionsupporting

confidence: 72%

Lack of Neuroprotective Effect of Celastrol Under Conditions of Proteasome Inhibition by Lactacystin in In Vitro and In Vivo Studies: Implications for Parkinson’s Disease

et al. 2014

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A number of studies suggest that the ubiquitin–proteasome system (UPS) impairment may underlie neuronal death in Parkinson’s disease. Celastrol is a neuroprotective agent with anti-inflammatory and antioxidant properties. The aim of this study was to determine whether celastrol may exert neuroprotective effects both in vitro and in vivo under conditions of the lactacystin-induced UPS inhibition. In the in vitro study, mouse primary cortical neurons and neuroblastoma SH-SY5Y cells were incubated with lactacystin for 48 h (2.5 and 10 μg/ml, respectively). The animal study was performed on male Wistar rats injected unilaterally with lactacystin (5 μg/2 μl) into the substantia nigra (SN) pars compacta. In the in vitro study, we did not found any protective effects of celastrol, given either in the pre- or co-treatment mode. Moreover, in the higher concentrations, celastrol itself reduced cell viability, and enhanced the lactacystin-induced cell death in both types of cells. In the in vivo study, none of the celastrol doses (0.3–3 mg/kg) attenuated the lactacystin-induced decrease in the level of dopamine (DA) and its metabolites or protected nigral dopaminergic neurons against the lactacystin-induced degeneration. The highest celastrol dose potentiated the lactacystin-induced decrease in the level of DA and its metabolites in the lesioned striatum, and accelerated the lactacystin-induced increase in the oxidative and total metabolism of DA. Moreover, when given alone, this dose of celastrol bilaterally decreased the number and/or density of dopaminergic neurons in the SN. Our results demonstrate that celastrol does not induce neuroprotective effects under conditions of UPS inhibition.

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Section: Discussionsupporting

confidence: 72%

Lack of Neuroprotective Effect of Celastrol Under Conditions of Proteasome Inhibition by Lactacystin in In Vitro and In Vivo Studies: Implications for Parkinson’s Disease

et al. 2014

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“…every 2 hr for a total of four injections, resulting in a cumulative dose of 80 mg/kg, as described previously [51]. Mirtazapine (generously provided by Meiji Seika Pharma Co., Ltd., Japan) was dissolved in 0.5% carboxymethylcellulose, and was applied once a day with 4 or 16 mg/kg i.p.…”

Section: Methodsmentioning

confidence: 99%

Mirtazapine has a therapeutic potency in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson’s disease

et al. 2014

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BackgroundMirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), shows multiple pharmacological actions such as inhibiting presynaptic α2 noradrenaline receptor (NAR) and selectively activating 5-hydroxytriptamine (5-HT) 1A receptor (5-HT1AR). Mirtazapine was also reported to increase dopamine release in the cortical neurons with 5-HT dependent manner. To examine whether mirtazapine has a therapeutic potency in Parkinson’s disease (PD), we examined this compound in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model of PD.ResultsMale C57BL/6 mice were subjected to MPTP treatment to establish a PD model. Mirtazapine was administered once a day for 3 days after MPTP treatment. MPTP-induced motor dysfunction, assessed by beam-walking and rota-rod tests, was significantly improved by administration of mirtazapine. Biochemical examinations by high performance liquid chromatography and western blot analysis suggested mirtazapine facilitated utilization of dopamine by increasing turnover and protein expression of transporters, without affecting on neurodegenerative process by MPTP. These therapeutic effects of mirtazapine were reduced by administration of WAY100635, an inhibitor for 5HT1AR, or of clonidine, a selective agonist for α2-NAR, or of prazosin, an inhibitor for α1-NAR, respectively.ConclusionOur results showed mirtazapine had a therapeutic potency against PD in a mouse model. Because PD patients sometimes show depression together, it will be a useful drug for a future PD treatment.

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“…The PSI groups received proteasome inhibitor I (Z-Ile-Glu(OtBu)-Ala-Leu-CHO), a cell-permeable reversible inhibitor of the chymotrypsin-like activity of the 20S proteasome, provided in 50 mM stock solution in DMSO (Calbiochem, La Jolla, CA). PSI was applied subcutaneously every other day over a period of 2 weeks at a concentration of 5 mg per kilo body weight per day in 1.7 % DMSO in saline as based on previous protocols and data [4, 13, 19, 22, 34, 36, 46]. The vehicle-treated groups received 1.7 % DMSO in saline according to the same time schedule.…”

Section: Methodsmentioning

confidence: 99%

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

et al. 2012

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Multiple system atrophy (MSA) is a progressive late onset neurodegenerative a-synucleinopathy with unclear pathogenesis. Recent genetic and pathological studies support a central role of a-synuclein (aSYN) in MSA pathogenesis. Oligodendroglial cytoplasmic inclusions of fibrillar aSYN and dysfunction of the ubiquitinproteasome system are suggestive of proteolytic stress in this disorder. To address the possible pathogenic role of oligodendroglial aSYN accumulation and proteolytic failure in MSA we applied systemic proteasome inhibition (PSI) in transgenic mice with oligodendroglial human aSYN expression and determined the presence of MSAlike neurodegeneration in this model as compared to wildtype mice. PSI induced open field motor disability in transgenic aSYN mice but not in wild-type mice. The motor phenotype corresponded to progressive and selective neuronal loss in the striatonigral and olivopontocerebellar systems of PSI-treated transgenic aSYN mice. In contrast no neurodegeneration was detected in PSI-treated wildtype controls. PSI treatment of transgenic aSYN mice was associated with significant ultrastructural alterations including accumulation of fibrillar human aSYN in the cytoplasm of oligodendroglia, which resulted in myelin disruption and demyelination characterized by increased g-ratio. The oligodendroglial and myelin pathology was accompanied by axonal degeneration evidenced by signs of mitochondrial stress and dysfunctional axonal transport in the affected neurites. In summary, we provide new evidence supporting a primary role of proteolytic failure and suggesting a neurodegenerative pathomechanism related to disturbed oligodendroglial/myelin trophic support in the pathogenesis of MSA.

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Proteasome Inhibitor Does Not Enhance MPTP Neurotoxicity in Mice

Cited by 11 publications

References 40 publications

Lack of Neuroprotective Effect of Celastrol Under Conditions of Proteasome Inhibition by Lactacystin in In Vitro and In Vivo Studies: Implications for Parkinson’s Disease

Lack of Neuroprotective Effect of Celastrol Under Conditions of Proteasome Inhibition by Lactacystin in In Vitro and In Vivo Studies: Implications for Parkinson’s Disease

Mirtazapine has a therapeutic potency in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson’s disease

Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human α-synuclein under oligodendrocyte promoter: implications for multiple system atrophy

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