EC:1.14.16.2 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.16.2 (tyrosine hydroxylase)
14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione levels are decreased in the substantia nigra of patients with Parkinson's disease. We studied whether glutathione depletion contributes to dopaminergic cell death using a specific inhibitor of glutathione biosynthesis, L-buthionine sulfoximine (BSO). We found no significant reduction of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta (SNpc) when BSO was administered systemically to preweanling mice or locally to the SNpc of adult rats. However, the combination of BSO with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in preweanling mice and the combination of nigral injections of BSO with intrastriatal injections of MPP+ (1-methyl-4-phenylpyridinium), the active metabolite of MPTP in adult rats, potentiated the toxic effects of MPTP and MPP+ on nigral neurones. Our data show that glutathione depletion can result in cell death if the nigrostriatal system is metabolically compromised.
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PMID:Glutathione depletion potentiates MPTP and MPP+ toxicity in nigral dopaminergic neurones. 872 74

The mechanism of the behavioral improvement observed in parkinsonian primates that receive intrastriatal transplants of fetal dopamine neurons has not been firmly established. Dopamine production by grafted neurons may be the basis of the behavioral recovery. Alternatively, stimulation of the host dopamine system by the transplant procedure itself may be central to the outcome. The present study examined whether dopamine concentration was raised in the caudate nucleus of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primate following grafting, and if so, whether the elevation was dependent on either (i) the introduction of the implantation cannula (sham), (ii) the brain region that was grafted, or (iii) the gestational age of fetal tissue that was grafted. Transplantation of early gestational age fetal ventral mesencephalon (embryonic days 40-50) was associated with significant elevation of caudate nucleus dopamine concentration to a mean of approximately 20% of control values in the vicinity (within 2 mm) of the graft, compared with more distant sites in the caudate nucleus. With early gestational age fetal ventral mesencephalon, the ratio of homovanillic acid/dopamine concentration near the graft site was normalized compared to the elevated value found in the caudate nucleus distant from the graft site. Grafts of later stage fetal ventral mesencephalon, or fetal cerebellum, or sham implantation did not increase dopamine concentration or lower homovanillic acid/dopamine ratio near the graft site. Biochemical and histochemical evidence suggests that host dopamine neurons terminating in the nucleus accumbens are not the source of the changes. Numerous tyrosine hydroxylase-positive neurons at the graft site were only observed in the MPTP-treated monkeys that received grafts of early gestational age fetal ventral mesencephalon. These data lend strong support to the hypothesis that dopamine derived from grafted dopamine neurons is the major basis for behavioral recovery observed following intrastriatal transplantation in our MPTP-treated monkeys.
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PMID:Early gestational mesencephalon grafts, but not later gestational mesencephalon, cerebellum or sham grafts, increase dopamine in caudate nucleus of MPTP-treated monkeys. 873 17

The ability of selegiline to protect against the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been attributed to the inhibition of the conversion of MPTP to 1-methyl-4-phenylpyridinium (MPP+), catalyzed by monoamine oxidase-B. Selegiline, however, has been found to rescue neurons in MPP(+)-treated mice after they have sustained lethal damage independently of monoamine oxidase-B inhibition. In our present study, we investigate whether selegiline can protect and/or rescue MPP(+)-injured dopaminergic neurons in co-cultures of mesencephalic and striatal cells of embryonic C57B1/6 mouse brains. Cells were exposed to selegiline (1, 10, 100 microM) in three different schemes: (i) in control cultures on the 8th day for 48 h; (ii) pretreatment: on the 8th day for 48 h, followed by administration of MPP+ (0.5 microM) on the 9th day for 24 h; (iii) delayed treatment: on the 9th day for 48 h, while MPP+ was administered on the 8th day and remained in culture during treatment with selegiline. In the delayed scheme, selegiline (1 microM) increased dopamine content, number of tyrosine hydroxylase immunoreactive cells and astrocytes in the cultures. We question whether selegiline protects cells injured by a toxic stressor via an astrocyte-mediated mechanism.
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PMID:Selegiline is neuroprotective in primary brain cultures treated with 1-methyl-4-phenylpyridinium. 881 31

We studied the microglial reaction in mice using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model for Parkinson's disease (PD). Microglial cells were identified by means of the Griffonia simplicifolia lectin (GSA-I-B4). Dopaminergic neurons were marked by tyrosine hydroxylase antibodies. Microglial activation was demonstrated by an increase in cellular number and changes of morphology (increased lectin staining, larger cell bodies and thicker processes) were seen in the substantia nigra from the 1st to the 14th day and in the striatum from the 1st to the 4th day after intoxication. Depletion of dopaminergic neurons was most pronounced 7 and 14 days following the treatment. The results suggest that microglial activation may be involved in the sequence of pathological changes that lead to dopaminergic neuronal damage after MPTP intoxication.
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PMID:Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease mice model. 881 34

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is the first representative of a new class of highly halogenated heterocycles. The similarity of the beta-carboline framework to the chemical structure of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prompted us to investigate the neurotoxic potential of this compound. For this purpose, primary cell cultures of C57/B16 mouse mesencephalon containing dopaminergic neurons were used. Cells were grown for 10 days and exposed to the toxin for 24 hours. The morphological changes observed in tyrosine hydroxylase immunoreactive (TH-IR) neurons and glial cells included swollen dendrites and soma, loss of axons and dendrites. At a TaClo concentration of 100 microM, the number of TH-IR neurons was decreased by 50%. In case of astrocyte cultures, changes became evident and at concentrations between 50-100 microM, a cell loss of 50% was observed. Furthermore, uptake of dopamine (DA) was reduced by 43% at 100 microM TaClo. Simultaneously, the DA content was significantly reduced by 66% at 100 microM.
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PMID:Studies of the potentially endogenous toxin TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) in neuronal and glial cell cultures. 882 Oct 62

The neuropathology of Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra. We have recently shown that the activation of protein kinase A improves the survival of dopaminergic neurons in culture and, furthermore, protects them from the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+) in vitro. We have now analysed the potential of phosphodiesterase inhibitors to increase cAMP levels in dopaminergic neurons, to improve their survival in culture and to protect them from the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo. Increasing intracellular cAMP with phosphodiesterase type IV-specific inhibitors enhanced the survival of dopaminergic neurons in culture. Inhibitors of other phosphodiesterase types were not active. In vivo, phosphodiesterase type IV inhibitors reduced the MPTP-induced dopamine depletion in the striatum of C57BL/6 mice. Furthermore, the loss of tyrosine hydroxylase-immunopositive neurons in the substantia nigra of these animals was diminished. After Nissl staining, a similar reduction of the MPTP-induced loss of neurons was observed in the substantia nigra. The protective effect of protein kinase A activation did not appear to be due to the blocking of MPP+ uptake into dopaminergic neurons. This was not decreased after treatment with forskolin or 8-(4-chlorophenylthio)-cAMP. Thus, protein kinase A regulates the survival and differentiation of dopaminergic substantia nigra neurons in vivo, implicating a therapeutic potential for substances which regulate cAMP turnover in these neurons.
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PMID:Inhibitors of type IV phosphodiesterases reduce the toxicity of MPTP in substantia nigra neurons in vivo. 884 48

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP+) are potential endogenous neurotoxins causing nigral cell death from Parkinson's disease. We now report the effects of 7 days unilateral supranigral infusion in rats of four isoquinoline derivatives, namely N-n-propylisoquinolinium (N-Pr-IQ+), N-methyl-6,7-dimethoxyisoquinolinium (N-Me-6,7-diOMe-IQ+), 6,7-dimethoxy-1-styryl-3,4-dihydroisoquinoline (6,7-diOMe-1-S-3,4-DHIQ) and 1,2,3,4-tetrahydroisoquinoline (THIQ) compared to MPP+. MPP+ (33 nmol/24h)-infused rats showed a marked reduction in motor activity and displayed ipsilateral postural asymmetry. Administration of apomorphine or (+)-amphetamine to these animals produced robust contralateral and ipsilateral rotations, respectively. In contrast, rats infused with the isoquinoline derivatives (150 nmol/24h) did not show spontaneous or drug-induced motor changes. Infusion of MPP+ decreased the number of tyrosine hydroxylase (TH)-positive cells in the ipsilateral substantia nigra pars compacta (SNc) by approximately 90%. Infusion of N-Me-diOme-IQ+ and THIQ produced approximately 42% and 20% ipsilateral SNc cell loss, respectively, but N-Pr-IQ+ and 6,7-diOMe-1-S-3,4-DHIQ did not alter SNc cell numbers. MPP+ markedly depleted the dopamine (DA, 95%), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) content of the ipsilateral striatum. N-Me-diOMe-IQ+ and THIQ also reduced the DA content of the ipsilateral striatum by approximately 39% and 20% respectively, but N-Pr-IQ+ and 6,7-diOme-1-S-3,4-DHIQ did not deplete striatal DA content. The isoquinoline derivatives slightly reduced (N-Me-diOMe-IQ+ and THIQ) or had no effect (N-Pr-IQ+ and 6,7-diOMe-1-S-3,4-DHIQ) on DOPAC or HVA levels. In conclusion, some isoquinoline derivatives that are substrates for the dopamine re-uptake system and inhibitors of mitochondrial function, are toxic to nigral dopaminergic neurones. Chronic exposure to endogenous or exogenous isoquinoline derivatives might contribute to cell death in Parkinson's disease.
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PMID:Nigral cell loss produced by infusion of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 891 Sep 5

The calcium-binding proteins Calbindin-D28k and calretinin are co-localized with dopamine in some of the midbrain dopaminergic neurons in the rat and monkey; the present study sought to examine the pattern of co-localization in the mouse. Double immunofluorescence staining procedures were used for tyrosine hydroxylase (a dopaminergic cell marker) and Calbindin-D28k or calretinin. Midbrain dopaminergic neurons were examined at four rostrocaudal levels, and the percentage of cells that contained both tyrosine hydroxylase and either of the two calcium-binding proteins was determined in nucleus A8 (retrorubral field), nucleus A9 (substantia nigra pars compacta, pars reticulata and pars lateralis) and nucleus A10 (nucleus paranigralis, ventral tegmental area, interfascicular nucleus, central linear nucleus). The two calcium-binding proteins were distributed similarly in midbrain dopaminergic neurons in the several nuclear groups that comprise nuclei A8, A9 and A10. The calcium-binding proteins were found in the majority (50-100%) of nucleus A10 neurons, whereas in nuclei A8 and A9 (except for the substantia nigra pars lateralis) less than 40% of the cells contained either calcium-binding protein. The pattern of co-localization in the mouse is similar to that reported for the rat and monkey. The calcium-binding proteins mark the population of midbrain dopaminergic neurons that are less vulnerable to degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
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PMID:Midbrain dopaminergic neurons in the mouse: co-localization with Calbindin-D28K and calretinin. 893 Oct 15

The present study was designed to evaluate the effects of 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine [(+)MK-801] on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage in the mouse, with the goal of clearly defining what protective effects, if any, this noncompetitive N-methyl-phenyl-1,2,3,6-tetrahydropyridine receptor antagonist may have against MPTP neurotoxicity. Animals were treated with MPTP (40 mg/kg s.c.) and/or (+)MK-801 (3 x 1 mg/kg i.p. at 4-hr intervals starting 30 min before MPTP) and were killed at 8 hr and 1, 7 and 21 days after MPTP exposure. Dopamine concentrations were measured in the striatum and ventral mesencephalon, and the total number of neurons in the substantia nigra was estimated using an unbiased stereological technique. Administration of (+)MK-801 before MPTP temporarily prevented MPTP-induced dopamine depletion. This was observed at 8 hr in the striatum and 1 week in the ventral mesencephalon, but not at other time-points studied. In both areas of the brain, (+)MK-801 appeared to delay the elimination of the metabolite 1-methyl-4-phenylpyridinium ion without affecting its formation. A 30% loss of nigral neurons with tyrosine hydroxylase immunoreactive and cresyl violet staining was seen at 1 and 3 weeks in both groups of MPTP-exposed animals, regardless of whether they received (+)MK-801. These data suggest that (+)MK-801 may affect the acute pharmacological/biochemical events induced by MPTP, but it does not have any enduring protective effects on either dopamine concentrations and/or the cell loss induced by this neurotoxin in mice.
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PMID:(+)MK-801 does not prevent MPTP-induced loss of nigral neurons in mice. 899 26

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Hypotheses concerning the mechanism of action of MPTP have been related to the pathogenesis of nigral cell death in Parkinson's disease. For instance, alterations of calcium influxes have been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease. Recently, we reported that nimodipine, a blocker of L-type calcium channels, prevents dopaminergic MPTP-induced neurotoxicity in C57B1/6 black mice. The present study extended these rodent findings to the non-human primate model of Parkinson's disease and assessed the effects of nimodipine, continuously applied by pellet for 18 days, on behavioural, biochemical and histological parameters, following systemic application of MPTP in common marmosets (Callithrix jacchus). The experimental design involved five groups of common marmosets and a total of 24 animals. Monkeys assigned to group I (n = 4) received subcutaneously implanted vehicle pellets 7 days prior to subcutaneous saline injections (control). Monkeys of group II (n = 4) were treated with nimodipine pellets (80 mg) and saline injections. Marmosets in group III (n = 8) were treated with vehicle pellets and received 4 times MPTP (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 h for a total of 4 days). Monkeys in group IV (n = 4) and V (n = 4) were treated as group-III animals except for the implantation of nimodipine pellets (80 mg and 120 mg, respectively) 7 days prior to toxin exposure. In common marmosets MPTP induced severe parkinsonian symptoms, a pronounced dopamine depletion in the caudate-putamen (more than 99% of control) and a loss of tyrosine hydroxylase immunoreactive cells in the substantia nigra (50% percent of control) 7 days after MPTP-administration. Pretreatment with nimodipine (120 mg pellets) did neither attenuate the behavioural impairments in MPTP-treated animals nor antagonize the striatal neurotoxin-induced dopamine depletion, but almost completely prevented (in a dose-dependent manner) the MPTP-induced decrease of nigral tyrosine hydroxylase immunoreactive cells. These data suggest that application of nimodipine, during the observation period of 7 days, protects against MPTP-induced neurotoxicity in common marmosets at the cellular nigral level, but not at the synaptic striatal level, implicating differential mechanisms of actions of MPTP-induced neurotoxicity at the nigral versus the striatal level.
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PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in non-human primates is antagonized by pretreatment with nimodipine at the nigral, but not at the striatal level. 900 22

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