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 pedunculopontine tegmental nucleus (PPTg) contains a population of cholinergic neurons thought to be part of the ascending reticular activating system, and non-cholinergic neurons. In the previous study it was shown that various excitotoxins made effective lesions of cholinergic neurons in the PPTg but that quinolinate made smaller lesions in the non-cholinergic population, making it more selective than any other excitotoxin. The purpose of the present experiment was, first, to make lesions of cholinergic neurons throughout the length of the PPTg by infusing toxin at two different sites within it; and second, to examine simple motor activities in rats bearing either quinolinate or ibotenate lesions of the PPTg, and contrast these with the deficits seen after 6-hydroxydopamine (6-OHDA) induced lesions of mesostriatal dopamine (DA)-containing neurons. Post-mortem examination was carried out using choline acetyltransferase (ChAT) and tyrosine hydroxylase (TOH) immunohistochemistry, and routine Nissl staining. Both quinolinate and ibotenate destroyed approximately 75% of ChAT-positive neurons in the PPTg, but damage to non-cholinergic neurons (assessed by Nissl staining) was twice as great following ibotenate as quinolinate. 6-OHDA induced almost complete lesions of mesostriatal DA neurons, assessed by TOH immunohistochemistry. DA depleted rats showed deficits in drinking and spilled more food in the first 2 weeks after surgery, and were unable to reach or grasp food pellets in the staircase test. They also showed strong ipsilateral turning in response to amphetamine and contralateral turning to apomorphine. Quinolinate lesioned rats had no eating or drinking impairment in the home cage but showed a reaching (though not grasping) disability in the staircase test. They had a mild ipsilateral bias following amphetamine. Ibotenate lesioned rats, despite having larger lesions than the quinolinate, showed no deficits in eating or drinking in the home cage, or reaching or grasping disabilities in the staircase test. They did have a mild contralateral bias in response to amphetamine. This dissociation of the effects of quinolinate and ibotenate lesions of the PPTg is consistent with the suggestion that the PPTg has two functionally distinct components, and is attributed to the differential lesion of non-cholinergic neurons by the two excitotoxins.
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PMID:Excitotoxic lesions of the pedunculopontine tegmental nucleus of the rat. II. Examination of eating and drinking, rotation, and reaching and grasping following unilateral ibotenate or quinolinate lesions. 135 93

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.
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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 neostriatum is one of the areas with relatively high levels of glial cell line-derived neurotrophic factor (GDNF) messenger RNA expression in the developing and adult brain. GDNF expression in the neostriatum has been suggested to be involved in promoting the survival of nigral dopaminergic neurons, acting as a target-derived neurotrophic factor. However, GDNF messenger RNA expression in the striatum starts several days before dopaminergic and other afferent neurons reach the striatum, suggesting additional trophic effects of this factor on striatal neurons. In the present report, we have examined whether GDNF is able to prevent the degeneration of striatal calbindin- and parvalbumin-immunoreactive neurons in a lesion model of Huntington's disease. Fischer 344 rat 3T3 fibroblast cell line expressing high levels of GDNF (F3A-GDNF) was used to assess the protective effect of this factor, on striatal neurons, against excitotoxicity. Quinolinate (34 nmol) was injected at two different coordinates, and calbindin, parvalbumin and tyrosine hydroxylase immunoreactivity were examined seven days after lesion. Dopaminergic afferents were spared after quinolinate injection, but the number of calbindin- and parvalbumin-immunoreactive neurons was decreased. Interestingly, implantation of F3A-GDNF cells increased the density of tyrosine hydroxylase staining in the intact and also in the quinolinate-lesioned striatum. Furthermore, GDNF partially protected calbindin- but not parvalbumin-immunoreactive neurons from quinolinate excitotoxicity. Instead, mock-transfected fibroblasts did not affect any of these parameters. Our results show that GDNF specifically protects a subpopulation of striatal calbindin-immunoreactive neurons against quinolinate lesion, suggesting that GDNF administration may have a potential therapeutic application in the prevention and treatment of striatonigral degenerative disorders.
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PMID:Glial cell line-derived neurotrophic factor protects striatal calbindin-immunoreactive neurons from excitotoxic damage. 893 Oct 1

Excitotoxins are valuable tools in neuroscience research as they can help us to discover the extent to which certain neurones are necessary for different types of behaviour. They have distinctive neurotoxic effects depending on where they are infused, and this study was conducted to delineate the neurotoxic profiles of excitotoxins in the laterodorsal tegmental nucleus (LDTg). Two 0.1 microl infusions of 0.1 M ibotenate, 0.1 M quinolinate, 0.04-0.1 M NMDA, or 0.05-0.015 M AMPA, were made unilaterally into the LDTg under either pentobarbitone or Avertin anaesthesia. The injection needle was oriented at an angle of 24 degrees from vertical in the mediolateral plane. After 23-27 days, sections through the mesopontine tegmentum were processed using standard histological procedures for NADPH-diaphorase histochemistry, tyrosine hydroxylase or 5-hydroxytryptamine immunohistochemistry, and Cresyl violet. Lesions were assessed in terms of the size of the damaged area (identified by reactive gliosis), the extent of cholinergic cell loss in the mesopontine tegmentum (by counting NADPH-diaphorase-positive neurones), and neuronal loss induced in the locus coeruleus and dorsal raphe nucleus. Ibotenate induced compact lesions in the LDTg (more than 80% cholinergic loss) and did little damage to the locus coeruleus and dorsal raphe nucleus. Quinolinate and low doses of AMPA and NMDA made very small lesions with less than 35% cholinergic loss, while at higher doses, AMPA and NMDA induced large areas of reactive gliosis but killed only a proportion of the cholinergic neurones. AMPA appeared to have a particular affinity for noradrenergic neurones in the locus coeruleus, with the 0.015 M dose injected into the LDTg typically destroying the majority of these neurones. The results are discussed in the context of what is known about the mechanisms of excitotoxins and the glutamate receptor profile of mesopontine neurones.
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PMID:Discriminable excitotoxic effects of ibotenic acid, AMPA, NMDA and quinolinic acid in the rat laterodorsal tegmental nucleus. 916 37