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

The behavioural, biochemical and morphological effects of a chronic administration of low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were studied in the common marmoset. Monkeys received the toxin (1 mg/kg i.p.) twice a week for four months. Group A monkeys were studied one week after the last injection of MPTP; group B monkeys were studied eight months after the last toxic injection. The monkey behaviour was observed throughout the experiment; the biochemical and morphological correlates were studied post mortem in the neostriatum and in the substantia nigra, respectively. Data collected from MPTP-treated marmosets were compared to those obtained from sham-injected control monkeys. The results can be summarized as follows. (1) In all MPTP-treated marmosets a progressive Parkinsonism occurred. In group B monkeys, a gradual behavioural recovery was observed after MPTP was discontinued. (2) Biochemical analysis of group A marmosets showed a depletion of dopamine, of 3,4-hydroxyphenylacetic acid and of homovanillic acid, and no variations in dopamine turnover in the neostriatum of MPTP-treated marmosets. In group B, biochemical analysis showed no differences between controls and MPTP-treated animals. (3) Morphological analysis showed that the density of midbrain dopaminergic neurons located in the substantia nigra was unchanged in group A monkeys, but was reduced by 6.8% in MPTP-treated monkeys of group B. The measurement of cross-sectional area showed that midbrain dopaminergic neurons were swollen in MPTP-treated monkeys of group A, with a 11.0% increase of cell size as compared to controls. In group A the nuclei were also swollen, being 304.8% larger in MPTP-treated monkeys, with a nucleus-to-cytoplasm ratio of 65.9% (as compared to 34.0% of controls). In group B monkeys cell size was increased by 18.4% in MPTP-treated marmosets, but the nuclei were of comparable size. The present data show that a chronic administration of low doses of MPTP brings about biochemical and morphological abnormalities. The first occur acutely in terminals and are reverted early after discontinuance of exposure to the toxin; the latter occur in dopaminergic perikarya, last longer than biochemical abnormalities and, at variance with them, increase in severity after MPTP is discontinued. Morphological abnormalities include early events, such as a transient swelling of nuclei or a long-lasting swelling of neurons, and late events, such as a decrease in the number of tyrosine hydroxylase-positive perikarya.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to monkeys: behavioural, morphological and biochemical correlates. 810 18

Studies have suggested that the restorative effects of adrenal medullary chromaffin cell grafts in animal models of Parkinson's disease may be related to trophic factors contained within the chromaffin cells. Basic fibroblast growth factor (bFGF) is present in chromaffin cells and has been shown to exert trophic effects on dopaminergic neurons in vitro. Basic FGF was stereotaxically injected into the striatum of young (2-month-old) and aging (12-month-old) C57BL/6 mice which had been treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 1 week earlier. MPTP treatment reduced tyrosine hydroxylase (TH)-immunoreactive (IR) fibers in the striatum and striatal dopamine (DA) concentration in both the young and older mice 5 weeks later. Computerized image analysis of striatal DA fibers in young mice treated with bFGF showed significant recovery of DA fibers up to 600 microns from the injection site 5 weeks after MPTP administration. Striatal DA fibers in older mice treated with bFGF showed significant recovery only up to 300 microns from the injection site, and the degree of recovery was very limited compared with young mice. HPLC analysis of DA concentration revealed that striatal DA in young mice recovered significantly when treated with bFGF, but no significant recovery was observed in older mice. It is concluded that bFGF enhances the recovery of striatal DA systems from MPTP toxicity both in young and in older mice, but that such benefits are very limited in older mice.
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PMID:Enhanced recovery of the nigrostriatal dopaminergic system in MPTP-treated mice following intrastriatal injection of basic fibroblast growth factor in relation to aging. 810 13

The effects of unilateral intracarotid administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in sheep were studied with the goal of producing a non-primate, large animal model of Parkinson's Disease. Adult female sheep were given an acute (over 30 min) or chronic (over 1 week) injection of MPTP (0.4-5.0 mg/kg) via the common carotid artery. Both methods produced parkinsonian-like behavior. Turning contralateral to the side of injection was induced by apomorphine (APO) in both groups. However, amphetamine (AMP) induced ipsilateral turning only in the chronic treatment group. Acute and chronic MPTP treatment resulted in a loss of substantia nigra tyrosine hydroxylase immunoreactive (THIR) neurons with a significantly greater loss ipsilateral to the injection in each treatment group (acute p < 0.05; chronic p < 0.01). Caudate dopamine (DA) was depleted in both treatment groups, although the difference between ipsilateral and contralateral DA content was significant only in the chronic treatment group (p < 0.05). The best results were seen in those animals with chronic infusion with the occipital artery occluded to prevent entry of drug into the posterior circulation with subsequent bilateral distribution. Use of slow and continuous intracarotid administration of MPTP with the ipsilateral occipital artery occluded can prevent some of the bilateral effects of acute treatment, and results in statistically significant ipsilateral reduction of THIR neurons in the substantia nigra and reduction of tissue levels of DA in the caudate nucleus. Such treatment produces appropriate turning responses to both AMP and APO challenge not seen in the acute treatment group, and appears to be an effective method of producing parkinsonian-like behavior in a large animal.
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PMID:Development of a model for Parkinson's disease in sheep using unilateral intracarotid injection of MPTP via slow continuous infusion. 830 50

Striatal 18F-6-fluorodopa (FD) uptake constants were measured by positron emission tomography in (1) normal cynomolgus monkeys and (2) a series of cynomolgus and rhesus monkeys that had received intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After the animals were killed, the number and average size of dopaminergic neurons in the substantia nigra pars compacta were measured. Striatal levels of dopamine and its metabolites, and the striatal activities of the dopaminergic synthetic enzymes, were also determined. The striatal FD uptake constants showed highly significant positive correlations with both number and size of dopaminergic neurons, indicating atrophy of surviving neurons in MPTP-treated animals. The uptake constants also showed significant positive correlations with striatal levels of dopamine, total catecholamines, and the activities of the synthetic enzymes. Both histochemical and biochemical data on tyrosine hydroxylase suggested some contralateral enzyme loss in these MPTP-treated monkeys, as well as decreased enzyme activity in surviving neurons on the lesioned side. However, residual enzyme activities were apparently not rate limiting to striatal FD uptake. It is concluded that PET-FD measurements by positron emission tomography provide a good index of the integrity of the nigrostriatal pathway.
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PMID:Correlation of striatal fluorodopa uptake in the MPTP monkey with dopaminergic indices. 836 50

The protective effect of GM1 ganglioside against nerve cell death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was analyzed in monkey mesencephalon. Administration of GM1 before and during MPTP treatment improved motor performances compared with MPTP-treated animals that received saline rather than GM1. Postmortem analysis revealed that GM1 did not protect dopaminergic cell bodies from MPTP intoxication but resulted in an increased immunoreactivity of tyrosine hydroxylase in the perikarya and processes of the surviving neurons. These data suggest that GM1 may be potentially used as a palliative rather than a curative therapy in Parkinson's disease.
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PMID:Gangliosides and parkinsonism. 841 79

The progressive degeneration of dopamine neurons observed in idiopathic Parkinson's disease was mimicked by injecting low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to baboons, on a chronic basis. Five Papio papio baboons were treated on two different regimens (chronic intravenous administration at weekly intervals for 20-21 months or, daily MPTP treatment for five days followed five to six months later by chronic weekly injections for 5-21.5 months). All animals were assessed for motor symptoms during and after neurotoxic treatment. Both regimens invariably resulted in the appearance of a progressive and irreversible syndrome characterized by action and resting tremor, cogwheel rigidity, postural impairments, hypokinesia and bradykinesia. In some animals, symptoms of resting tremor and rigidity initially restricted to one side of the body became bilateral within a few months of treatment. Subtle abnormalities that may be found in idiopathic Parkinson's disease such as alterations of the blink reflex response were also noted. Neuropathological examination of caudate nucleus, putamen, substantia nigra and ventral tegmental area in brain sections stained for tyrosine hydroxylase showed a typical uneven striatal dopamine fibre loss and a neuronal depletion in the dopaminergic mesencephalic cell groups that reproduce those observed in idiopathic Parkinson's disease. Immunocytochemical observations and behavioural data show that chronic rather than acute MPTP injection regimens can replicate most of the neuropathological and the clinical features typical of idiopathic Parkinson's disease, possibly by increasing the ability of this neurotoxin to target specific subpopulations of mesencephalic dopaminergic neurons.
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PMID:Stable parkinsonian syndrome and uneven loss of striatal dopamine fibres following chronic MPTP administration in baboons. 846 5

Mechanisms responsible for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine (DA) neuronal death remain unknown and in mice it is even unclear whether neuronal death does occur. In vitro studies suggest that 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP, kills neurons by apoptosis. Herein, we investigated whether MPTP induces DA neuronal death in vivo in mice and whether the mechanism is that of apoptosis. C57/bl Mice received different doses of MPTP administered in four intraperitoneal injections every 2 hours and were sacrificed at different time points for analyses of tyrosine hydroxylase (TH) immunohistochemistry, silver staining, and Nissl staining within the mesencephalon. We found that MPTP induces neuronal destruction in the substantia nigra pars compacta (SNpc) and the ventral tegmental area (VTA). The active phase of degeneration began at 12 h postinjection and continued up to 4 days. During this period, there was a greater decrease in TH-defined neurons than in Nissl-stained neurons suggesting that MPTP can cause a loss in TH without necessarily destroying the neuron. Thereafter, neuronal counts by both techniques equalized and there was no further loss of DA neurons. Dying neurons showed shrunken eosinophilic cytoplasm and shrunken darkly stained nuclei. Double staining revealed degenerating neurons solely among TH positive neurons of SNpc and VTA. At no time point and at no dose of MPTP was apoptosis observed. In addition, in situ labelling revealed no evidence of DNA fragmentation. This study demonstrates that the MPTP mouse model replicates several key features of neurodegeneration of DA neurons in PD and provides no in vivo evidence that, using this specific paradigm of injection, MPTP kills DA neurons by apoptosis.
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PMID:Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 858 58

Rapid chronoamperometric recordings, using Nafion-coated carbon-fiber electrodes (30-90 microns o.d.), were used to investigate overflow and uptake of dopamine (DA) in the striatum of normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys. The monkeys were anesthetized with isoflurane and placed in a stereotaxic apparatus. Magnetic resonance imaging-guided sterile stereotaxic procedures were used for implantations of the electrochemical electrodes coupled with single-barrel micropipettes that were used to apply potassium or DA locally. Potassium evoked a robust overflow of DA-like electrochemical signals into the brain extracellular space in the unlesioned or normal putamen and caudate nucleus of the rhesus monkeys. In contrast, potassium did not produce any detectable changes (> 97% depletion) of DA in the MPTP-lesioned striatum. In addition, the diffusion/clearance of locally applied DA was markedly altered in the lesioned caudate nucleus and putamen compared with unlesioned striatum. Cell counts of the number of residual tyrosine hydroxylase-positive neurons in MPTP-treated monkeys, in conjunction with whole-tissue levels of DA and its metabolites, showed that the MPTP lesions produced extensive damage of the nigrostriatal DA system. These data indicate that residual dopaminergic fibers remaining after MPTP lesions are dysfunctional and have a greatly diminished capacity for high-affinity DA uptake.
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PMID:In vivo electrochemical studies of dopamine overflow and clearance in the striatum of normal and MPTP-treated rhesus monkeys. 859 27

The ability of PC12 cells to regenerate processes is substantially enhanced in vitro if they have been previously exposed to nerve growth factor (NGF-primed), compared to cells that have not been exposed (NGF-naive). These studies were carried out to determine if the enhanced neuritogenic ability of NGF-primed cells is retained following transplantation. NGF-naive or NGF-primed PC12 cells were transplanted into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and allowed to survive for 2 weeks. Mice were given daily injections of cyclosporin A (CyA) to prevent anti-species graft rejection. The transplanted PC12 cells were visualized by tyrosine hydroxylase immunoreactivity. The NGF-naive transplanted cells formed dense clusters and large tumor masses in more than half the animals. Only a few of the naive PC12 cells had short processes. In contrast, many of the transplanted NGF-primed PC12 cells had processes. Furthermore, fewer of the animals transplanted with primed cells produced tumor masses in the striatum compared to animals that received NGF-naive cells. Transplantation of NGF-naive PC12 cells leads to a significant increase in the number of dopaminergic neurons in the host substantia nigra (SN) compared to MPTP-treated animals. The increase of host dopaminergic neurons was not statistically significant when NGF-primed PC12 cells were used. Following MPTP treatment and PC12 cell transplantation, injection of CyA did not affect the dopaminergic neurons in the host SN. These data suggest that exposure of cells to trophic factors, prior to transplantation, can enhance their level of differentiation and integration into the host brain.
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PMID:The effect of prior in vitro exposure of donor cells to trophic factors in neurotransplantation. 859 97

We have previously shown that muscle-derived differentiation factors (MDF) and human recombinant acidic fibroblast growth factor (aFGF) have beneficial behavioral and neurochemical effects on the nigrostriatal dopaminergic neurons of 6-hydroxy-dopamine (6-OHDA)-lesioned rats (Jin and Iacovitti: Neurobiol Dis 2:1-12, 1995). In the present study, we determined the effects of similar treatments on mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Five days after unilateral striatal infusion of MDF or aFGF into MPTP-lesioned mice, striatal tyrosine hydroxylase (TH) activity and dihydroxyphenylacetic acid (DOPAC) levels were bilaterally increased (20-35%) compared to untreated (lesion only) or control (phosphate buffered saline + bovine serum albumin) mice. These increases, however, were not accompanied by change in dopamine (DA) levels, indicating an elevation of DA synthesis (TH/DA) and turnover (DOPAC/DA). The present findings that MDF and aFGF may have neurochemical effects in vivo on the lesioned nigrostriatal dopaminergic system suggest their potential pharmacological role in the treatment of Parkinson's disease.
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PMID:Dopamine differentiation factors increase striatal dopaminergic function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice. 871 21


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