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)

Chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to baboons was shown previously to result in a motor syndrome and a pattern of striatal dopaminergic fibre loss similar to those observed in idiopathic Parkinson's disease. In the present study, tyrosine hydroxylase-immunoreactive neurons were quantified in the mesencephalon of control (n = 4) and chronically MPTP-treated (n = 3) baboons. MPTP induced a significant reduction in neuronal cell density in the substantia nigra (63.8% reduction) and the ventral tegmental area (53.1%). Within the substantia nigra, obvious mediolateral and dorsoventral gradients of neuronal cell loss were observed. First, the pars lateralis was more affected than the lateral divisions of the pars compacta (89.6% vs 73.8% cell loss), which in turn were more depleted than the medial divisions (60.1% reduction). Second, the ventral regions of the pars compacta were more degenerated than the dorsal parts (82.4 vs 51.5% decrease). This regional pattern is strikingly similar to that observed in Parkinson's disease and indicates that two subpopulations of dopaminergic neurons are distinguishable on the basis of their differential vulnerability to MPTP. Finally, the present study confirms that chronic mitochondrial complex I inhibition using MPTP in primates is sufficient to reproduce the typical dopaminergic cell loss and striatal fibre depletion observed in Parkinson's disease.
 ...
PMID:Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in Parkinson's disease. 789 60

We have examined the influence of chronic GM-1 treatment (20 mg/kg i.m. for 16 consecutive days) on the extent of dopaminergic damage induced by acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in cynomolgus monkeys using immunohistochemical and neurochemical analysis. The total number of tyrosine hydroxylase-immunoreactive neurons was reduced in different catecholaminergic mesencephalic regions of MPTP-treated monkeys such as substantia nigra pars compacta, mainly in the ventral portion of the nucleus (39% reduction), substantia nigra pars lateralis (31%), peri- and retrorubral catecholaminergic cell group and ventral tegmental area (A8 and A10 respectively, 20% reduction). A similar degree of neuronal loss was observed in the MPTP+GM-1-treated animals, suggesting that GM-1 ganglioside does not exert a protective effect against MPTP-induced dopaminergic cell loss. Moreover, no neurochemical recovery from the striatal dopaminergic depletion induced by MPTP was found after GM-1 treatment. However, the optical density of tyrosine hydroxylase fibers and the cellular tyrosine hydroxylase content were increased in the substantia nigra pars compacta and ventral tegmental area of the MPTP-treated monkeys which received GM-1 ganglioside, compared with animals treated only with the neurotoxin. These results indicate that GM-1 does not protect against cell death but exerts a neurotrophic effect on surviving dopaminergic neurons in the midbrain of MPTP-lesioned monkeys, suggesting that GM-1 ganglioside may be potentially useful for the treatment of neurodegenerative disorders such as Parkinson's disease.
 ...
PMID:GM-1 ganglioside promotes the recovery of surviving midbrain dopaminergic neurons in MPTP-treated monkeys. 790 32

Intrastriatal implantation with dopaminergic of nondopaminergic tissue can elicit behavioral recovery in parkinsonian animals. Because in these animals, especially in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, there are still considerable numbers of dopaminergic neurons left in the mesencephalon, implantation-induced trophic effects on host residual dopaminergic neurons have been suggested as a mechanism underlying the behavioral recovery. Gliosis around the graft is a universal finding in any implantation procedure and is probably mediated by interleukin-1 (IL-1); in addition, activated astrocytes secrete several neurotrophic factors in vitro. Therefore, the authors postulated that trophic effects from IL-1-induced gliosis may be a "final common pathway" for recovery in parkinsonian animals after implantation. Hemiparkinsonism was induced in rats by injection of 6-hydroxydopamine either directly into the substantia nigra or into the median forebrain bundle. The substantia nigra-lesioned rats showed complete depletion of dopaminergic neurons in the substantia nigra but sparing of those in the ventral tegmental area, whereas the median forebrain bundle-lesioned animals had depletion of dopaminergic cells in the substantia nigra and the ventral tegmental area. Polymer pellets containing either slow-released IL-1 alpha and beta or placebo pellets were implanted in the caudate nucleus on the lesioned side in both groups. The rats' rotational response to amphetamine was tested weekly for 8 weeks. Selective substantia nigra-lesioned rats with implantation of IL-1 pellets had a 45% reduction in amphetamine-induced rotation, whereas placebo-implanted substantia nigra-lesioned rats had a 14% reduction in rotation. In the median forebrain bundle-lesioned group, neither IL-1 nor placebo implantation elicited any effect on turning. Immunohistochemical staining for glial fibrillary acidic protein was markedly increased surrounding the IL-1 pellets compared to the placebo pellets. In the selective substantia nigra-lesioned rats with IL-1 pellets implanted in the caudate nucleus, a considerable number of tyrosine hydroxylase immunoreactive (TH-IR) fibers were observed in the medial and middle portions of the caudate nucleus. Fewer TH-IR fibers were seen in the rats with placebo-bearing pellets. These results suggest that neurotrophic activities mediated by IL-1 and reactive astrocytes might be a common path through which tissue trauma and some tissue transplants exert their beneficial effects in parkinsonian animals. Furthermore, most of the sprouted dopaminergic fibers induced by IL-1 in the caudate nucleus come from dopaminergic neurons in the ventral tegmental area.
 ...
PMID:Intrastriatal implantation of interleukin-1. Reduction of parkinsonism in rats by enhancing neuronal sprouting from residual dopaminergic neurons in the ventral tegmental area of the midbrain. 790 26

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease.
 ...
PMID:The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates. 790 75

Parkinson's disease is characterized by the degeneration of melanized dopaminergic neurons of the substantia nigra. The functional capacity of the surviving dopaminergic neurons is affected, as suggested by the subnormal levels of tyrosine hydroxylase messenger RNA and protein found in the remaining cells. The reduced expression of tyrosine hydroxylase may be due to either the evolving neurodegenerative process or its downregulation, possibly secondary to chronic levodopa treatment. The cellular content of tyrosine hydroxylase was determined in the mesencephalon from 16 Macaca fascicularis monkeys, using a semiquantitative immunocytochemical method. Thirteen monkeys were rendered parkinsonian by weekly intravenous injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 2 (subacute treatment) or 20 (chronic treatment) weeks. Three of the monkeys received levodopa and 3 others received GM1 ganglioside. The loss of dopaminergic neurons in the mesencephalon of the MPTP-intoxicated monkeys was severe in the substantia nigra, intermediate in cell groups A8 and A10, and almost undetectable in the central gray substance. After both subacute and chronic treatment, the cellular content of tyrosine hydroxylase was reduced by 40% in the surviving neurons of the lesioned substantia nigra, but by less in the other mesencephalic dopaminergic regions. Neuronal survival and tyrosine hydroxylase content in monkeys that had received levodopa were not significantly different. The cellular content of tyrosine hydroxylase was increased in the substantia nigra of the monkeys that received GM1 ganglioside injections. The results show that the decreased expression of tyrosine hydroxylase found in nigral dopaminergic neurons after partial degeneration of the mesostriatal dopaminergic system is not influenced by levodopa treatment and is partially reversed by GM1 ganglioside administration.
 ...
PMID:Decreased tyrosine hydroxylase content in the dopaminergic neurons of MPTP-intoxicated monkeys: effect of levodopa and GM1 ganglioside therapy. 791 99

Administration of the irreversible cholinesterase inhibitor isoflurophate (diisopropylfluorophosphate, DFP) before 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) enhanced the loss in tyrosine hydroxylase activity and dopamine and 3,4-dihydroxy-phenylacetic acid content in the striatum of mice in a dose-dependent manner. The effect of DFP on the MPTP-induced changes of dopaminergic markers was evident 30 days after initiating treatment, suggesting augmented neurotoxicity. Neurotoxicity was also enhanced by prior treatment with nicotine, carbachol or oxotremorine. We conclude that activation of either muscarinic or nicotinic receptors enhances the neurotoxicity of MPTP.
 ...
PMID:Enhanced MPTP neurotoxicity after treatment with isoflurophate or cholinergic agonists. 791 17

Cross-species neural grafting of cell lines immunoisolated by a permselective polymer membrane represents a promising source of neuroactive molecules for the treatment of neurodegenerative diseases. Utilization of a cell line of xenogeneic origin is advantageous since the transplanted cells will be rejected by the host immune system in case of breakage of the immunoisolating envelope. Polymer-encapsulated PC12 cells, a dopaminergic cell line derived from a rat pheochromocytoma, were transplanted in five Macaca fascicularis monkeys which had been previously rendered hemiparkinsonian by a unilateral carotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Well-preserved, tyrosine hydroxylase positive encapsulated PC12 cells were observed in the lesioned striatum for up to 5 months after implantation. Four out of five monkeys which received polymer-encapsulated PC12 cells showed significant behavioral improvement, whereas three monkeys implanted with either encapsulated bovine chromaffin cells or empty polymer envelopes showed no amelioration.
 ...
PMID:Functional recovery in hemiparkinsonian primates transplanted with polymer-encapsulated PC12 cells. 792 16

The present study demonstrates that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes significantly greater reductions in striatal dopamine levels in C57/bl mice than in CD-1 mice, thus confirming a greater sensitivity of the C57/bl mice to MPTP. To determine the possible reasons for this difference in MPTP sensitivity between these two mouse strains, we have compared both the organization and the number of substantia nigra (SN) neurons, the primary target of MPTP, in C57/bl and in CD-1 mice using immunostaining for tyrosine hydroxylase (TH) and calbindin-D28k (calbindin). In saline-injected animals, there is a significantly lower number of SN TH-positive and calbindin-positive neurons in C57/bl than CD-1 mice; no significant differences in the numbers of these neurons are found in the ventral tegmental area between the two strains. In MPTP-injected animals, the reductions in SN TH-positive neurons are significantly greater in C57/bl than in CD-1 mice. In contrast, MPTP does not cause any significant changes in the numbers of SN calbindin-positive neurons in either strain. The present study shows that C57/bl mice which have fewer SN TH-positive neurons are more sensitive to MPTP-induced toxicity than CD-1 mice. This observation suggests a possible inverse relationship between SN TH-positive neuron number and MPTP sensitivity. If correct, this hypothesis may be of major importance for Parkinson's disease since it is suggested that individuals at risk of developing this neurodegenerative disorder may have lower numbers of SN TH-positive neurons to start with. The present study also shows that SN calbindin-positive neurons are spared following MPTP administration. However, the observed difference in SN calbindin-positive neuron numbers does not account for the differential sensitivity to MPTP between these two mouse strains.
 ...
PMID:Differences in nigral neuron number and sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57/bl and CD-1 mice. 792 20

The toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, intravitreally injected in goldfish eye, involves interplexiform retinal neurons and depletes tyrosine hydroxylase immunoreactivity and dopamine levels. This induced neurotoxicity was prevented by the concomitant administration in non-toxic doses (10 micrograms) of quinolinic acid, an endogenous structural analogue of N-methyl D-aspartate with excitotoxic properties. Quinolinic acid is ineffective on the retinal degeneration induced by 1-methyl-4-phenylpyridinium ion. This fact suggests that quinolinic acid inhibits the MAO-B oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. MK-801, a noncompetitive antagonist of glutamate NMDA-receptors, exerts partial protective effects on MPTP-induced delayed toxicity in mammals. In the goldfish eye, MK-801, injected in low concentration, and in conjunction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium ion, did not prevent retinal neurodegeneration. Ten micrograms of MK-801 alone did not affect retinal neurons, while a higher concentration (20 micrograms) causes the chromatolysis of some photoreceptor nuclei.
 ...
PMID:Quinolinic acid but not MK-801 protects the dopaminergic system from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced toxicity in goldfish retina. 798 38

The protective role of basic fibroblast growth factor (FGF-2) for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and methylpyridiniumion (MPP+)-lesioned dopaminergic (DAergic) nigrostriatal neurons was studied, using dissociated cell cultures of embryonic day (E) 14 rat mesencephalon. Cells were grown in different culture media and received FGF-2 (5 ng/ml) and/or the toxins (5 microM) at various schedules, but were consistently allowed to differentiate for 3 days prior to becoming exposed to the toxin. Survival of tyrosine hydroxylase (TH)-immunoreactive cells at 7 days was only markedly impaired by MPTP, if horse serum (HS) or bovine serum albumin (BSA) were omitted from the culture medium. FGF-2 increased the number of TH-immunoreactive cells, and this increase was not diminished by MPTP under any culture condition. Uptake of 3H-DA was significantly reduced by MPTP in HS- and BSA-containing, but not in protein-less cultures. A protective effect by FGF-2 was only seen in the presence of BSA. MPP+ caused a more pronounced reduction in 3H-DA uptake than MPTP, and this effect was partially reversed by the addition of FGF-2, unless cultures contained HS. Neurofilament protein (NF), and indirect measure for the total number of neurons present in the cultures, was not significantly reduced by MPTP or MPP+ corroborating the specificity of the toxin for DAergic neurons, which constitute only a minor fraction in these cultures. In line with the wide spectrum of target neurons of FGF-2, this factor significantly increased NF contents under any culture condition. Quantification of the amounts of glial fibrillary acidic protein (GFAP) revealed stimulatory effects of FGF-2 (2.5- to 4-fold) and at least 10-fold higher levels in the presence as compared to the absence of HS. These data show that FGF-2 can protect DAergic neurons against MPTP- and MPP(+)-mediated damage. However, the effects of the toxins as well as of FGF-2 are partially dependent on culture conditions. Variations in the effectiveness of toxins and FGF-2 are not overtly related to the total numbers of neurons or astroglial cells, but may reflect culture type-dependent alterations of neuronal and glial metabolism.
 ...
PMID:FGF-2-mediated protection of cultured mesencephalic dopaminergic neurons against MPTP and MPP+: specificity and impact of culture conditions, non-dopaminergic neurons, and astroglial cells. 809 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>