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.

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.

Dysfunction of the proteasome function is known to be a potential mechanism for dopaminergic neuron degeneration. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI), causes the increased susceptibility in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. PSI was injected into MPTP-treated mice over a period of 2 weeks. Thereafter, we evaluated the effect of PSI 2, 4, and 8 weeks after the cessation of treatment with PSI. In the present study with HPLC analysis, PSI did not enhance MPTP-induced dopaminergic neurotoxicity in mice. Our present study with Western blot analysis also demonstrated that the reduction of tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP) protein levels in MPTP-treated mice was more pronounced than that in MPTP + PSI-treated animals. These results suggest that proteasome inhibitor did not enhance MPTP neurotoxicity in mice. Our findings suggest that proteasome inhibition is not a reliable model for PD. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease.

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We investigated to determine whether acute administration of proteasome inhibitor can cause dopaminergic cell loss in mice, in comparison with that of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The four intraperitoneally administrations of MPTP at 1-h intervals to mice decreased significantly the concentration of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum after 5 days, in comparison with vehicle-treated animals. In contrast, the three subcutaneously administrations of carbobenzoxy-L-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal (PSI) did not show significant changes in the concentration of dopamine, DOPAC and HVA in the striatum after 5 days, in comparison with vehicle-treated animals. Our Western blot analysis also showed that the four administrations of MPTP at 1-h intervals to mice produced a significant reduction of anti-tyrosine hydroxylase antibody (TH) protein levels in the striatum after 5 days after. In PSI-treated mice. In contrast, no significant change of TH protein levels was observed in the striatum 5 days after the final treatment with PSI. Furthermore, a significant decrease of TH protein levels was observed in the striatum of MPTP-treated mice, as compared with PSI-treated animals. The present study demonstrates that the acute treatment with proteasome inhibitor PSI did not cause the dopaminergic neurotoxicity in mice, as compared with acute treatment with MPTP. Thus, our findings suggest that acute proteasome inhibition is not a reliable model for Parkinson's disease.

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2016-12-23T18:49:38