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 autoxidation of L-DOPA or dopamine (DA) and the metabolism of DA by monoamine oxidase generate a spectrum of toxic species, namely, hydrogen peroxide, oxy radicals, semiquinones, and quinones. When primary dissociated cultures of rat mesencephalon were incubated with L-DOPA (200 microM) for 48 h, the number of tyrosine hydroxylase-positive neurons (DA neurons) was reduced to 69.7% of control values, accompanied by a decrease in [3H]DA uptake to 42.3% of control values; the remaining DA neurons exhibited reduced neurite length and overall deterioration. Lack of simultaneous change in the number of neurons stained with neuron-specific enolase indicated that toxicity was relatively specific for DA neurons. At the same time, the level of GSH, a major cellular antioxidant, rose to 125.2% of control values. Thus, exposure of mesencephalic cultures to L-DOPA results in both damaging and antioxidant actions. Ascorbate (200 microM), an antioxidant, prevented the rise in GSH. The effect of ascorbate on GSH points to an oxidative signal to initiate the rise in GSH content. On the other hand, neither inhibition of monoamine oxidase with pargyline nor addition of superoxide dismutase or catalase to the culture medium prevented the rise in GSH level or the loss in [3H]DA uptake. The latter results tend to exclude the products of monoamine oxidase activity or the presence of hydrogen peroxide or superoxide in the medium as responsible agents for the rise in GSH or neuronal toxicity. In cultures treated with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, L-DOPA prevented cell death by L-BSO.
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PMID:Toxic and protective effects of L-dopa on mesencephalic cell cultures. 837 99

Nigral cell death in Parkinson's disease (PD) may involve oxidative stress and mitochondrial dysfunction initiated by a decrease in reduced glutathione (GSH) levels in substantia nigra. L-buthionine-(S,R)-sulphoximine (BSO; 4.8 and 9.6 mg/kg/day), an irreversible inhibitor of gamma-glutamyl cysteine synthetase, was chronically infused into the left lateral ventricle of rats over a period of 28 days and markedly reduced GSH concentrations in substantia nigra (approx. 59% and 65% in 4.8 and 9.6 mg/kg/d BSO respectively) and the striatum (approx. 63% and 80% in 4.8 and 9.6 mg/kg/d BSO respectively). However, the number of tyrosine hydroxylase (TH)-positive cells in substantia nigra was not altered by BSO-treatment compared to control animals. Similarly, there was no difference in specific [3H]-mazindol binding in the striatum and nucleus accumbens of BSO-treated rats compared to control rats. In conclusion, depletion of GSH following chronic administration of BSO in the rat brain does not cause damage to the nigrostriatal pathway and suggests that loss of GSH alone is not responsible for nigrostriatal damage in PD. Rather, GSH depletion may enhance the susceptibility of substantia nigra to destruction by endogenous or exogenous toxins.
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PMID:Glutathione depletion in rat brain does not cause nigrostriatal pathway degeneration. 908 94

The neuroprotective effect of intermittent hypoxia on ferrous citrate (iron)-induced oxidative stress was investigated in the nigrostriatal dopaminergic system of rat brain. Female Wistar rats were subjected to 380 mm Hg in an altitude chamber for 15 h/day for 7, 14, or 28 days. Iron was locally infused in the substantia nigra of anesthetized rats. Seven days after infusion, lipid peroxidation was elevated in the infused substantia nigra and dopamine content and tyrosine hydroxylase-positive axons were decreased in the ipsilateral striatum in the normoxic rats. Intermittent hypoxic treatment prevented iron-induced oxidative injuries. Induction of the neuroprotection required 2 weeks. Intracerebroventricular infusion of L-buthionine-[S,R]-sulfoximine (L-BSO), which mimicked a reduced antioxidative condition, aggravated iron-induced oxidative injuries. Intermittent hypoxia ameliorated L-BSO-induced augmentation of iron-induced oxidative injuries. Basal GSH (glutathione) content, GSH/GSSG ratio, superoxide dismutase (SOD) and catalase activities in intact substantia nigra were not altered by intermittent hypoxia. Furthermore, intermittent hypoxia attenuated iron-induced reductions in GSH content, GSH/GSSG ratio, and SOD, iron-induced increase in catalase but had no effect on glutathione peroxidase. Our data suggest that intermittent hypoxia may protect the nigrostriatal dopaminergic system from iron-induced oxidative injuries. Moreover, antioxidative defensive systems may partially contribute to the neuroprotection by intermittent hypoxia.
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PMID:Neuroprotective effect of intermittent hypoxia on iron-induced oxidative injury in rat brain. 1235 74

This study provides the first evidence for catecholamine synthesis and release in the RAW264.7 cell line, an important macrophage model. Although catecholamines were low in unstimulated cells, activation with lipopolysaccharide (LPS) induced tyrosine hydroxylase (TH) mRNA and increased extracellular norepinephrine and intracellular dopamine within 48 h. The catecholamine synthesis inhibitor alpha-methyl-para-tyrosine (alpha-mpt) decreased extracellular norepinephrine levels, suggesting release and rapid turnover of newly synthesized norepinephrine. High concentrations of dopamine or norepinephrine (>/=100 microM) decreased proliferation and increased apoptosis of macrophages. These anti-proliferative effects were prevented by simultaneous treatment with the anti-oxidant ascorbic acid. Pre-incubation with a glutathione synthesis inhibitor (L-buthionine-[S,R]-sulfoximine [L-BSO]) increased sensitivity to catecholamine-stimulated apoptosis, suggesting that glutathione protects macrophages from both endogenous and exogenous catecholamines.
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PMID:Catecholamines in a macrophage cell line. 1257 23

Sympathetic activities are elevated in the central SNSs (sympathetic nervous systems) of hypertensive animals, but it is not known whether sympathetic innervation is also elevated in the heart. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress. The aim of the present study was to investigate sympathetic hyperinnervation in DOCA (deoxycorticosterone acetate)-salt hypertensive rats with established hypertension. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, NAC (N-acetylcysteine) and triple therapy (hydralazine, hydrochlorothiazide and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, as assessed by myocardial noradrenaline levels, immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and Western blotting and real-time quantitative RT-PCR (reverse transcription-PCR) of NGF (nerve growth factor). Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on BP (blood pressure), offered neither attenuated cardiomyocyte hypertrophy nor anti-arrhythmia. The effects of DOCA-salt treatment on NGF expression, sympathetic hyperinnervation and arrhythmias were attenuated by NAC. Furthermore, the effects of NAC on NGF were abolished by administering BSO (L-buthionine sulfoximine), an inhibitor of glutamate-cysteine ligase. In conclusion, DOCA-salt treatment contributes to up-regulation of NGF proteins probably through a free radical-dependent pathway in a BP-independent manner. DOCA-salt rats treated with NAC attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation.
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PMID:Cardiac sympathetic hyperinnervation in deoxycorticosterone acetate-salt hypertensive rats. 2250 72

In the present study, primary mesencephalic cell cultures prepared from embryonic mouse mesencephala were used to investigate the neuroprotective effect of cabergoline, an ergoline D2 receptor agonist, against the pesticide and neurotoxin rotenone relevant to Parkinson disease (PD). Treatment of cultures with cabergoline alone significantly increased the number of tyrosine hydroxylase immunoreactive (THir) neurons and reduced the release of lactate dehydrogenase (LDH) into the culture medium compared to untreated controls. Against rotenone toxicity, cabergoline significantly rescued degenerating THir neurons, reduced the release of LDH into the culture medium and improved the morphology of surviving THir neurons. The neuroprotective effects afforded by cabergoline were independent of dopaminergic stimulation as blocking of dopamine receptors by the dopamine receptor antagonist sulpiride did not prevent them. Furthermore, rotenone-induced formation of reactive oxygen species (ROS) was significantly reduced by cabergoline. Although cabergoline increased the glutathione (GSH) content in the culture, the protective effect for dopaminergic neurons seemed not to be predominantly mediated by increasing GSH, as depletion of GSH by L-buthionine-(S,R)-sulfoximine (BSO), a GSH biosynthesis inhibitor, did not prevent cabergoline-mediated neuroprotection of THir neurons in rotenone-treated cultures. Moreover, cabergoline significantly increased the ATP/protein ratio in primary mesencephalic cell cultures when added alone or prior to rotenone treatment. These results indicate a neuroprotective effect of cabergoline for dopaminergic neurons against rotenone toxicity. This effect was independent of dopamine receptor stimulation and was at least partially mediated by reducing ROS production and increasing the ATP/protein ratio.
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PMID:Cabergoline protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture. 2590 73