Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The catecholaminergic systems of sudden infant death syndrome victims were examined in the diencephalon and basal ganglia, in addition to the midbrain, pons, and medulla oblongata, using the immuno-histochemical method involving tyrosine hydroxylase. A significant decrease in tyrosine hydroxylase immunoreactivity was demonstrated in the basal ganglia of sudden infant death syndrome victims between 2 to 12 months of age compared with age-matched control subjects. This change in the basal ganglia may be a secondary finding induced by chronic hypoxia or repeated ischemia in sudden infant death syndrome but suggests impairment of the development of the neuronal connection from the brainstem to the upper cardiorespiratory control in sudden infant death syndrome.
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PMID:Catecholaminergic neurons in the diencephalon and basal ganglia of SIDS. 1042 33

Recently, we have reported that glial cell line-derived neurotrophic factor (GDNF), which supports the survival of dopaminergic neurons, prevents delayed neuronal death in the hippocampal CA1 region induced by transient forebrain ischemia. In the present study, we examined the role of GDNF in the expression of tyrosine hydroxylase (TH) mRNA induced by transient forebrain ischemia in rats. The expression of TH mRNA was increased in a time-dependent manner, with a significant increase in 24 h to 7 days, in the hippocampus after induction of transient forebrain ischemia, as determined using the reverse transcription and polymerase chain reaction method. Although it has been suggested that the increase of dopamine beta-hydroxylase mRNA expression correlates with the activation of noradrenergic neurons, no increase of dopamine beta-hydroxylase mRNA in the hippocampus was observed in our system. Western blot analysis revealed that TH protein, but not dopamine beta-hydroxylase protein, was produced in a time-dependent manner in the hippocampus during the ischemia. Interestingly, the induction level of TH mRNA was reduced by intrahippocampal microinjection of GDNF (1.0 microg), and this local GDNF treatment also reduced the increase of TH-like immunohistochemistry-positive terminals in the hippocampus. In contrast, local GDNF treatment of normal rats increased the TH mRNA expression at 6-12 h. These findings suggest that GDNF protects against neuronal degeneration including delayed neuronal death in the hippocampal CA1 region by modulating the expression levels of TH mRNA and protein.
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PMID:Glial cell line-derived neurotrophic factor modulates ischemia-induced tyrosine hydroxylase expression in rat hippocampus. 1088 42

(-)-Deprenyl, used for the treatment of Parkinson's disease, was reported to possess neurorescuing/antiapoptotic effects independent of its MAO-B inhibiting properties. It is metabolized to (-)-desmethyldeprenyl, which seems to be the active principle, and further to (-)-amphetamine and (-)-methamphetamine, which antagonize its rescuing effects. These complications may explain the limited neurorescuing potential of (-)-deprenyl observed clinically. CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine), structurally related to (-)-deprenyl, exhibits virtually no MAO-B nor MAO-A inhibiting properties and is not metabolized to amphetamines. It was shown to bind to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme with multiple other functions including an involvement in apoptosis, and shows neurorescuing properties qualitatively similar to, but about 100-fold more potent than those of (-)-deprenyl in several in vitro and in vivo paradigms. In concentrations ranging from 10(-13)-10(-5) M, it rescues partially differentiated PC12 cells from apoptosis induced by trophic withdrawal, cerebellar granule cells from apoptosis induced by cytosine arabinoside, rat embryonic mesencephalic dopaminergic cells from death caused by MPP+, and PAJU human neuroblastoma cells from death caused by rotenone. However, it did not affect apoptosis elicited by a variety of agents in rapidly proliferating cells from thymus or skin or in liver or kidney cells. In vivo, it rescued facial motor neuron cell bodies in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia, and mouse nigral dopaminergic cell bodies from death induced by MPTP, in doses ranging between 0.0003 and 0.1 mg/kg p.o. or s.c., depending on the model. It also partially prevented the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra of 6-OHDA-lesioned rats and improved motor function in these animals. Moreover, it prolonged the life-span of progressive motor neuronopathy (pmn) mice (a model for ALS), preserved their body weight and improved their motor performance. This was accompanied by a decreased loss of motor neurons and motor neuron fibers, and protection of mitochondria. The active concentration- or dose-ranges in the different in vitro and in vivo paradigms were remarkably similar. In several paradigms, bell-shaped dose-response curves were observed, the rescuing effect being lost above about 1 mg/kg, a fact that must be considered in clinical investigations.
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PMID:Neurorescuing effects of the GAPDH ligand CGP 3466B. 1120 40

The role of c-Fos in neurodegeneration or neuroprotection after cerebral ischemia is controversial. To investigate whether early c-Fos induction after ischemia is associated with neuroprotection, rats were subjected to 10 minutes of transient forebrain ischemia and c-Fos expression was examined. Resistant dentate granule cells and neurons in CA2-4 displayed more robust immunoreactivity than vulnerable neurons in the CA1 region of hippocampus during early hours of reperfusion. By 6 hours after reperfusion, c-Fos immunoreactivity was greatly diminished in all areas of the hippocampus. Administration of N-acetyl-O-methyldopamine (NAMDA), a compound previously shown to protect CA1 neurons against ischemia, increased c-Fos immunoreactivity in the CA1 vulnerable region at 6 hours after ischemia and protected SK-N-BE(2)C neurons from oxygen glucose deprivation. Further in vitro study showed that NAMDA potentiated phorbol-12 myristate-13 acetate (PMA)-induced c-Fos expression, AP1 binding activity, and late gene expression determined by chloramphenicol acetyltransferase (CAT) activity from AP1 containing tyrosine hydroxylase promoter-CAT fusion gene in SK-N-BE(2)C neurons. In vivo and in vitro results showed that a neuroprotectant, NAMDA, in concert with another stimulus (for example, ischemia or PMA) up-regulates c-Fos expression and suggested that the early rise of NAMDA-induced c-Fos expression in vulnerable CA1 neurons may account for neuroprotection by means of up-regulating late gene expression for survival.
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PMID:Early c-Fos induction after cerebral ischemia: a possible neuroprotective role. 1133 65

Hypoxia and ischemia regulate the expression of several important genes at the level of transcription and of mRNA stability. Two isoforms of a 40-kDa poly(C)-binding protein, previously identified as RNA-binding proteins, bind to a hypoxia-inducible protein-binding site in the 3'-untranslated region of erythropoietin and tyrosine hydroxylase mRNAs and regulate mRNA stability. To determine if poly(C)-binding proteins show changes in expression -- which might regulate mRNA stability -- in hypoxic or ischemic neuronal cells, we examined poly(C)-binding protein 1 and poly(C)-binding protein 2 expression in hypoxic cortical neuron cultures and in rat cerebral cortex after focal ischemia. Reverse transcription-polymerase chain reaction and western blotting showed hypoxic up-regulation of poly(C)-binding protein 1, and down-regulation of poly(C)-binding protein 2, mRNA and protein expression. Hypoxia-inducible expression of poly(C)-binding protein 1 was mediated by p38 mitogen-activated protein kinase, while hypoxia-reducible expression of poly(C)-binding protein 2 was mediated by protein kinase C. Immunostaining showed that poly(C)-binding protein 1, but not poly(C)-binding protein 2, expression was increased in the ischemic boundary zone (penumbra) of the frontal cortex after 90 min of ischemia, and persisted for at least 72 h after reperfusion. These results demonstrate that poly(C)-binding protein 1 and poly(C)-binding protein 2 in cortical neurons are differentially affected by hypoxic/ischemic insults, suggesting that there are functional differences between poly(C)-binding protein isoforms. Since we observed no poly(C)-binding protein expression in astroglia, alternative mRNA stability mechanisms may exist in these cells.
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PMID:Expression of poly(C)-binding proteins is differentially regulated by hypoxia and ischemia in cortical neurons. 1195 62

In the present study, we investigated the protective effects of the topical beta-adrenoceptor antagonist Betoptic((R)) (0.25% betaxolol) in the rat retina following the ischemic injury induced by a transient increase of intraocular pressure (IOP). Like other areas of the central nervous system, the retina is highly vulnerable to ischemic-induced injury. Ischemia was induced in the rat retina by raising the IOP above the systolic blood pressure for 60min. After an ischemia/reperfusion, the thickness of the retinal layers and the immunoreactivities of choline acetyltransferase (ChAT), gamma-amino butyric acid (GABA) and tyrosine hydroxylase (TH) were examined. After a reperfusion period of 7 days, the thickness of both the inner plexiform layer and inner nuclear layer was much decreased. After a reperfusion period of 14-28 days, the thickness of the outer nuclear layer decreased markedly. Moreover, the ChAT and TH immunoreactivity had almost completely disappeared in the retinas after 7 days, while GABA immunoreactivity remained for 28 days. These results suggest that the inner retinal layers are more susceptible to ischemic-induced injury than the outer retinal layer.Histological examination demonstrated protective effects of betaxolol on ischemic-induced retinal damage, which was more substantial in the inner retinal layer. When two drops of betaxolol, once before ischemic injury and twice daily for 28 days after ischemia, were continuously administered, the reductions in the retinal ChAT, GABA and TH immunoreactivities were significantly attenuated. The present study suggests that topically applied betaxolol is an efficient neuroprotective agent and prevents the retinal cell damage induced by ischemic injury in rats.
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PMID:Betaxolol, a beta1-adrenoceptor antagonist, protects a transient ischemic injury of the retina. 1245 71

There is only limited morphologic information on long-term alterations and neurotransmitter changes after perinatal asphyxia, and no long-term study showing neurodegeneration has been reported so far. We used an animal model for perinatal asphyxia well documented in the rat to investigate the guinea pig as a species highly mature at birth. Cesarean section was performed on full-term pregnant guinea pigs, and pups, still in membranes, were placed into a water bath at 37 degrees C for asphyxia periods from 2 to 4 min. Thereafter pups were given to surrogate mothers and examined at 3 mo of age. We studied brain areas reported to be hypoxia-sensitive. Neurodegeneration was evaluated by fluoro-jade, neuronal loss by Nissl, reactive gliosis by glial fibrillary acidic protein staining, and differentiation by neuroendocrine-specific protein C immunoreactivity. We tested tyrosine hydroxylase, the vesicular monoamine transporter, and dopamine beta-hydroxylase, representing the monoaminergic system; the vesicular acetylcholine transporter; and the excitatory amino acid carrier 1. Neurodegeneration was evident in cerebellum, hippocampal area CA1, and hypothalamus, and neuronal loss could be observed in cerebellum and hypothalamus; gliosis was observed in cerebellum, hippocampus, hypothalamus, and parietal cortex; dedifferentiation was found in hypothalamus and striatum; and monoaminergic, cholinergic, and amino acidergic deficits were shown in several brain regions. The major finding of the present study was that neurodegeneration and dedifferentiation evolved in the guinea pig, a species highly mature at birth. The relevance of this contribution is that a simple animal model of perinatal asphyxia resembling the clinical situation of intrauterine hypoxia-ischemia and presenting with neurodegeneration was characterized.
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PMID:Neurodegeneration, neuronal loss, and neurotransmitter changes in the adult guinea pig with perinatal asphyxia. 1286 99

Diadenosine tetraphosphate (AP4A), an endogenous diadenosine polyphosphate, reduces ischemic injury in the heart. In this study, we report the potent and protective effects of AP4A in rodent models of stroke and Parkinson's disease. AP4A, given intracerebroventricularly before middle cerebral artery (MCA) ligation, reduced cerebral infarction size and enhanced locomotor activity in adult rats. The intravenous administration of AP4A also induced protection when given early after MCA ligation. AP4A suppressed terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) induced by hypoxia/reperfusion in primary cortical cultures, and reduced both ischemia-induced translocation of mitochondrial cytochrome c and the increase in cytoplasmic caspase-3 activity in vivo. The purinergic P2/P4 antagonist di-inosine pentaphosphate or P1-receptor antagonist sulfonylphenyl theophylline, but not the P2-receptor antagonist suramin, antagonized the effect of AP4A, suggesting that the observed protection is mediated through an anti-apoptotic mechanism and the activation of P1- and P4-purinergic receptors. AP4A also afforded protection from toxicity induced by unilateral medial forebrain bundle injection of 6-hydroxydopamine (6-OHDA). One month after lesioning, vehicle-treated rats exhibited amphetamine-induced rotation. Minimal tyrosine hydroxylase immunoreactivity was detected in the lesioned nigra or striatum. No KCl-induced dopamine release was found in the lesioned striatum. All of these indices of dopaminergic degeneration were attenuated by pretreatment with AP4A. In addition, AP4A reduced TUNEL in the lesioned nigra 2 d after 6-OHDA administration. Collectively, our data suggest that AP4A is protective against neuronal injuries induced by ischemia or 6-OHDA through the inhibition of apoptosis. We propose that AP4A may be a potentially useful target molecule in the therapy of stroke and Parkinson's disease.
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PMID:Diadenosine tetraphosphate protects against injuries induced by ischemia and 6-hydroxydopamine in rat brain. 1294 27

The temporal profiles of the changes of dopaminergic cells and microglial activation induced by transient cerebral ischemia were investigated in the substantia nigra pars compacta (SNc) located outside ischemic areas of rat brain. Transient cerebral ischemia was induced by intraluminal occlusion of the right middle cerebral artery for 2 h and reperfusion was continued for 1, 2, 3, 4, 7, 10, 14, 28, 60, and 120 days. Dopaminergic cells immunostained with tyrosine hydroxylase (TH)-antibody in the ipsilateral SNc were significantly decreased at 7 days post-ischemia compared with those in the contralateral side (P<0.05). However, at 60 and 120 days, there were no significant differences between ipsilateral and contralateral side of the SNc. Unlike the TH immunoreactivity, activated microglial cells immunostained with OX-42 antibody were significantly increased at 2 and 3 days and then decreased gradually until 10 days post-ischemia. Activated microglial cells were increased at 2 weeks post-ischemia, and this pattern remained until 60 days. These results suggest that the transient changes of TH-immunoreactive cells in the SNc caused by transient focal ischemia are correlated with a biphasic microglial cell activation response.
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PMID:Microglial activation and tyrosine hydroxylase immunoreactivity in the substantia nigral region following transient focal ischemia in rats. 1294 87

Hypoxia-ischemia during the perinatal period causes excitotoxic lesions in sensitive brain areas, such as the striatum. The impact of hypoxia-ischemia on nigral neurons is less well known. Hypoxia alone, a less traumatic event without overt histological sequelae, has neuroprotective properties when used as a preconditioning stimulus. In some pathologies, injured neurons of the nigrostriatal system in the adult may be the result of neurodegenerative processes that originated at early stages of life. The effects of hypoxia on the immunoreactivity to tyrosine hydroxylase of the dopaminergic neurons of the substantia nigra pars compacta and the effects of a period of hypoxia previous to an excitotoxic lesion were examined by means of histological and Western blot methods, at immediate and late periods of the episode. By counting the number of tyrosine hydroxylase-stained neurons and c-fos-positive nuclei a short period after injection of quinolinic acid into the striatum, we observed that hypoxia induced a more marked decrease in the number of tyrosine hydroxylase-stained neurons. On the contrary, c-fos-positive profiles decreased in the substantia nigra pars reticulata of the quinolinic acid-injected animals after the preconditioning hypoxia. Hypoxia alone did not affect the number of tyrosine hydroxylase-positive neurons in the pars compacta nor did hypoxia induce c-fos expression in the pars reticulata. More sensitive Western blot analysis of tissue blocks that included the whole substantia nigra demonstrated the same trend as the immunohistochemical results. We conclude that the responses of the substantia nigra neurons to hypoxia are regionalized and potential neuroprotective effects may depend on the vulnerability of each neuronal type.
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PMID:c-fos and tyrosine hydroxylase expression after an excitotoxic lesion on the nigrostriatal system: a study on the effects of hypoxia used as a preconditioning stimulus. 1455 93


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