Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Failure of acute administration with proteasome inhibitor to provide a model of Parkinson's disease in mice. 1842 68

Genital dysfunction and testosterone deficiency occur frequently in Parkinson's disease and represent a typical non-motor symptom of the disorder. Despite that, to our knowledge no study investigated whether at experimental level this can be reproduced with classic Parkinsonism-inducing neurotoxins. In this study we evaluated the effects produced in the testis following administration of the Parkinsonism-inducing neurotoxin 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine in mice. At 7 days following treatment, in the presence of a severe nigrostriatal dopamine depletion, we found a marked decrease in testosterone plasma levels in 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine-treated mice. Such testosterone loss occurred concomitantly with loss of Leydig cells and the presence of altered morphology in the interstitium with severe mitochondrial degeneration in spared Leydig cells. The loss of Leydig cells was accompanied by a marked decrease in TH immunohistochemistry and TH protein in the interstitium. This was accompanied by a significant decrease in norepinephrine levels in the testis. These effects shed novel light to understand genital dysfunction and testosterone deficiency in Parkinsonism, while offering a new experimental model to reproduce genital dysfunction in Parkinson's disease.
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PMID:MPTP-induced Parkinsonism is associated with damage to Leydig cells and testosterone loss. 1864 55

Administering uridine-5'-monophosphate (UMP) and docosahexaenoic acid (DHA) increases synaptic membranes (as characterized by pre- and post-synaptic proteins) and dendritic spines in rodents. We examined their effects on rotational behavior and dopaminergic markers in rats with partial unilateral 6-hydroxydopamine (6-OHDA)-induced striatal lesions. Rats receiving UMP, DHA, both, or neither, daily, and intrastriatal 6-OHDA 3 days after treatment onset, were tested for d-amphetamine-induced rotational behavior and dopaminergic markers after 24 and 28 days, respectively. UMP/DHA treatment reduced ipsilateral rotations by 57% and significantly elevated striatal dopamine, tyrosine hydroxylase (TH) activity, TH protein and synapsin-1 on the lesioned side. Hence, giving uridine and DHA may partially restore dopaminergic neurotransmission in this model of Parkinson's disease.
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PMID:Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson's disease. 1876 83

Parkinson's disease (PD) is neurodegenerative diseases caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. Stem cell therapy is one of the promising strategies in helping to cure PD. In the present study, human mesenchymal stem cells (MSCs) from eye conjunctiva stromal cells were differentiated into dopaminergic neurons. In this work, after conjunctiva biopsy, mesenchymal stem cells were obtained via adherence to the plastic culture dishes. Then, MSCs were treated with general neurogenic medium containing DMEM supplemented with RA, IBMX and dbcAMP for 6 days. RT-PCR, immunocytochemistry and flow cytometry were used for expression of dopaminergic genes such as TH. As a result, RT-PCR analysis revealed the expression of dopaminergic neuron genes such as TH, Ptx3, Nurr1. Furthermore, immunocytochemistry revealed that the differentiated CJMSCs not only express TH gene, but also express TH protein. Flow cytometry showed that TH, MAP-2 proteins increased significantly as increasing passage number. In conclusion, the reported results indicate that CJMSCs might be a suitable and available source for cell transplantation therapy for the central system diseases such as PD.
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PMID:Expression of dopamine-associated genes on conjunctiva stromal-derived human mesenchymal stem cells. 1885 50

The effect of atipamezole, an alpha-2-adrenergic antagonist, was examined on the expression of tyrosine hydroxylase, the rate-limiting enzyme of synthesis of catecholamines such as dopamine, in the rat striatum. It has been reported that the alpha-2-adrenergic pathways can modulate the levodopa- and apomorphine-induced dopaminergic turning behavior in the rat model of Parkinson's disease. It is also known that catecholamines have a feed back inhibition of TH activity. Since atipamezole can increase the levodopa-induced turning behavior, a potential feed back effect on the TH enzyme was estimated by measuring the TH protein. In the present study, the atipamezole and/or levodopa treatments did not clearly affect on the amount of TH in the rat striata when measured by Western blot. However, it is possible that the sensitivity of the method limits the detection of changes, and therefore further studies are needed to examine the potential of atipamezole and/or levodopa effects on the regulation of TH enzyme, e.g., by measuring the phosphorylation status, activity and mRNA expression of TH enzyme.
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PMID:Expression of tyrosine hydroxylase in the striatum of atipamezole-treated rats. 1915 82

Zonisamide, an anti-convulsant drug, has recently been shown to exert beneficial effects in Parkinson's disease (PD). However, actual pathophysiological mechanism underlying the anti-parkinsonian effect of zonisamide remains uncertain. Here we tested exactly the neuroprotective effect of zonisamide against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. We observed that zonisamide attenuated MPTP-induced dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) depletion in the striatum and reduced the loss of tyrosine hidroxylase (TH) positive neurons and the increase of glial fibrillary acidic protein (GFAP) positive astrocytes in the striatum and substantia nigra after 5 days. Our Western blot analysis study also showed that zonisamide can prevent the decrease of TH protein levels and increase of GFAP protein levels in the striatum 5 days after MPTP treatment. In the present study, on the other hand, zonisaimde treatment showed no significant changes of the striatal dopamine, DOPAC, and HVA content in the striatum of normal mice after 1 day, as compared to the vehicle-treated group. Furthermore, zonisamide produced a significant increase of the TH protein levels in the striatum after 1 day, as compared to vehicle-treated group. In contrast, zonisamide showed no significant changes of the GFAP protein levels in the striatum after 1 day, as compared to vehicle-treated group. These results show that anticonvulsant drug, zonisamide, has the neuroprotective effect in the MPTP model of PD in mice. Our study also demonstrates that the neuroprotective effect of zonisamide against dopaminergic cell damage may be mediated by the elevation of TH activity on dopaminergic system after MPTP treatment in mice. Our findings suggest that zonisamide may offer a new approach for the treatment of PD.
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PMID:A novel anti-Parkinsonian agent, zonisamide, attenuates MPTP-induced neurotoxicity in mice. 1919 78

Decreased availability or efficacy of neurotrophic factors may underlie an increased susceptibility of mesencephalic dopaminergic cells to age-related degeneration. Neuregulins (NRGs) are pleotrophic growth factors for many cell types, including mesencephalic dopamine cells in culture and in vivo. The functional NRG receptor ErbB4 is expressed by virtually all midbrain dopamine neurons. To determine if levels of the NRG receptor are maintained during aging in the dopaminergic ventral mesencephalon, expression of ErbB4 mRNA and protein was examined in young (3 months), middle-aged (18 months), and old (24-25 months) Brown Norway/Fischer 344 F1 rats. ErbB4 mRNA levels in the substantia nigra pars compacta (SNpc), but not the adjacent ventral tegmental area (VTA) or subtantia nigra pars lateralis (SNl), were significantly reduced in the middle-aged and old animals when compared to young rats. Protein expression of ErbB4 in the ventral midbrain was significantly decreased in the old rats when compared to the young rats. Expression of tyrosine hydroxylase (TH) mRNA levels was significantly reduced in the old rats when compared to young animals in the SNpc, but not in the VTA or SNI. TH protein levels in the ventral midbrain were also decreased in the old animals when compared to the young animals. These data demonstrate a progressive decline of ErbB4 expression, coinciding with a loss of the dopamine-synthesizing enzyme TH, in the ventral midbrain of aged rats, particularly in the SNpc. These findings may implicate a role for diminished NRG/ErbB4 trophic support in dopamine-related neurodegenerative disorders of aging such as Parkinson's disease.
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PMID:Decreased expression of ErbB4 and tyrosine hydroxylase mRNA and protein in the ventral midbrain of aged rats. 1950 38

The aim of this study was to investigate the impact of gender difference in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animal model of Parkinson's disease (PD). In the present study, we investigated the time-dependent alterations of dopamine and its metabolites, striatal tyrosine hydroxylase (TH) protein, dopamine transporter (DAT) protein, glial fibrillary acidic protein (GFAP) protein and midbrain TH protein and motor function in male and female mice 5h and 1, 3 and 7 days after four administrations of MPTP (20mg/kg) at 2-h intervals. The present study showed that the decrease of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) content in female mice was more pronounced than that in male animals 1, 3 and 7 days after MPTP treatment. Our Western blot analysis study also demonstrated that the decrease of both striatal and midbrain TH protein levels in female mice was more pronounced than that in male animals from 1 to 7 days after MPTP treatment. As compared to male mice, in contrast, the increase of striatal GFAP protein levels in female mice was observed from 5h to 7 days after MPTP treatment. Furthermore, the present study showed that motor deficits were found in both male and female mice 1 and 7 days after MPTP treatment. In the present study, moreover, the decrease of striatal DAT protein levels in female mice was more pronounced than that in male animals 1, 3 and 7 days after MPTP treatment. These results demonstrate that our administrations of MPTP at 2-h intervals can cause more severe damage in female mice as compared with male animals. The gender difference may be due to the decrease of DAT expression caused by MPTP. Thus our findings provide further valuable information for the pathogenesis of PD.
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PMID:Gender differences on MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in C57BL/6 mice. 1963 14

Tyrosine hydroxylase (TH) is a rate-limiting enzyme for the biosynthesis of catecholamines including dopamine. The relationship between proteasomal dysfunction and the etiology of Parkinson's disease has been suggested, but it is unknown if TH protein is affected by proteasomal dysfunctions. Here, we examined the effect of inhibition of ubiquitin-proteasomal pathway on biochemical characteristics of TH protein in the neuronal cells. Inhibition of 20S or 26S proteasome by proteasome inhibitor I, or MG-132 in NGF-differentiated PC12D cells induced dot-like immunoreactivities with the anti-(40)Ser-phosphorylated TH (p40-TH) antibody. These dots were tightly co-localized with ubiquitin and positive to Thioflavine-S staining. These dot-like immunoreactivities were not obvious when immunostaining was performed against total-TH or choline acetyltransferase. Western blotting analysis showed time-dependent increase of p40-TH in the Triton-insoluble fractions. We also examined the effect of okadaic acid, an inhibitor of protein phosphatase 2A, which is a phosphatase acting on p40-TH. Okadaic acid increased the amount of insoluble p40-TH. These data suggest that p40-TH is prone to be insolubilized and aggregated by dysfunction of an ubiquitin-proteasome system in PC12D cells.
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PMID:Accumulation of phosphorylated tyrosine hydroxylase into insoluble protein aggregates by inhibition of an ubiquitin-proteasome system in PC12D cells. 1975 65

MSCs (mesenchymal stem cells) derived from the bone marrow have shown to be a promising source of stem cells in a therapeutic strategy of neurodegenerative disorder. Also, MSCs can enhance the TH (tyrosine hydroxylase) expression and DA (dopamine) content in catecholaminergic cells by in vitro co-culture system. In the present study, we investigated the effect of intrastriatal grafts of MSCs on TH protein and gene levels and DA content in adult intact rats. When MSCs were transplanted into the striatum of normal rats, the grafted striatum not only had significantly higher TH protein and mRNA levels, but also significantly higher DA content than the untransplanted striatum. Meanwhile, the grafted MSCs differentiated into neurons, astrocytes and oligodendrocytes; however, TH-positive cells could not be detected in our study. These experimental results offer further evidence that MSCs are a promising candidate for treating neurodegenerative diseases such as Parkinson's disease.
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PMID:Intrastriatal grafts of mesenchymal stem cells in adult intact rats can elevate tyrosine hydroxylase expression and dopamine levels. 1994 46


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