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 mechanisms underlying the response of the brain to ischemia are not fully understood. Biochemical and morphological changes following neocortical infarction can be investigated in rats using a model of focal cerebral ischemia induced by unilateral occlusion of the middle cerebral artery (MCA). Evaluation of ischemic damage often employs conventional histologic stains. Immunocytochemistry can be used as a valuable tool in this model to define changes in specific proteins of interest. In this study, an antiserum raised against insulin-like growth factor II (IGF-II) receptor was used to evaluate changes of IGF-II receptor immunoreactivity in the cerebral cortex of rats 4 and 7 days following permanent MCA occlusion. IGF-II receptor immunoreactivity was found to be associated with neocortical pyramidal neurons within the core of the ischemic infarct itself. The staining intensity was markedly elevated above that observed in nonischemic neurons. Immunopositive neurons exhibited a punctate staining pattern. These neurons appeared to correspond to argentophilic neurons, as defined by modified Bielschowsky silver staining. Evaluation of other neuronal markers revealed the absence of immunoreactivity for neuron-specific enolase and for tyrosine hydroxylase within the ischemic area. These observations show an increase in a specific growth factor receptor within neurons in the ischemic core of a focal infarct several days following permanent focal infarction, a time when neurons are presumed to be dead. The significance and the potential role of IGF-II receptor in lesion-induced plasticity are discussed.
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PMID:Increase in insulin-like growth factor II receptor within ischemic neurons following focal cerebral infarction. 759 34

Transforming growth factors beta are multifunctional proteins and regulators of cell proliferation and differentiation. Transforming growth factor-beta s have the capacity to rescue adult neurons from ischemia- and glutamate-induced cell death and are prominent in the embryonic and adult brain including striatum and substantia nigra. In the present study we show that transforming growth factors-beta 1, -2, and -3 promote, in a dose-dependent fashion, in vitro survival of tyrosine hydroxylase-immunoreactive dopaminergic neurons isolated from the embryonic rat mesencephalon floor. The magnitude of the effect, which was half-maximal at a concentration of 20 pM, was identical for all three transforming growth factor-isoforms and matched that of fibroblast growth factor-2. Unlike fibroblast growth factor-2, however, transforming growth factor-beta s did not increase numbers of astroglial cells visualized by using antibodies to glial fibrillary acidic protein, and had no effect on cell proliferation monitored by incorporation of BrdUrd. Transforming growth factor-beta s were significantly more potent than fibroblast growth factor-2 in protecting dopaminergic neurons against N-methyl-4-phenylpyridinium ion toxicity. RT-PCR analysis indicated that the effect of transforming growth factor-beta s is not mediated by glial cell-derived neurotrophic factor, which was not detectable in cultures at various time points. On the other hand transforming growth factor-beta 2 mRNA could be detected in freshly isolated and cultured mesencephalic cells, and its immunoreactivity has also been demonstrated in the embryonic day 14 mesencephalon floor. We conclude that transforming growth factor-beta has trophic and protective effects on developing dopaminergic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transforming growth factor-beta promotes survival of midbrain dopaminergic neurons and protects them against N-methyl-4-phenylpyridinium ion toxicity. 770 May 16

Motility disturbances following prolonged intestinal obstruction have been attributed to secondary effects. This study aimed to demonstrate the effects of incomplete obstruction on the enteric nervous system (ENS) of a rat model. Surgical placement of a nonstrangulating ligature encircling the distal bowel was performed in 41 freshly weaned rats. Anesthetic protocol included Ketamine, ether, or Xylazine (an alpha 2-adrenergic agonist). Histological evaluation was by ganglion cell morphology, histochemical staining for acetylcholinesterase (AChE) and tyrosine hydroxylase (TOH) immunocytochemistry. Forty-one freshly weaned LE rats were divided into controls (8), sham procedures (8), intestinal obstruction (16), and a group of rats with colonic biopsy performed prior to and following experimental obstruction (9). The rats were sacrificed at periods varying between 14 and 45 days post experimental obstruction (median survival, 27 days). Histological changes included elongation of ganglion cells and a decrease in the number per 5-mm slide in obstructed animals. No other obstruction specific differences were detected. A significant (P < .01) increase in AChE in the submucous plexus was recorded in Xylazine-anesthetized animals. No obstruction-specific effects could be demonstrated in the ENS, suggesting that prolonged obstruction without ischemia does not result in any significant alterations in the ENS. Pharmacological stimulation of the alpha 2-adrenergic receptor appeared to result in an increase in AChE. This mechanism may help to explain a possible role for the adrenergic system in the increased AChE levels in affected bowel in patients with Hirschsprung's disease.
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PMID:Secondary effects of prolonged intestinal obstruction on the enteric nervous system in the rat. 790 22

Time-dependent changes in the tissue concentration of tyrosine hydroxylase (TH), adrenaline (A), noradrenaline (NA), and neuropeptide Y (NPY) in the early stages of cerebral ischemia were studied immunohistochemically in the amygdaloid complex of rats subjected to 1 h cerebral ischemia. Immunoreactivity to TH on the lesioned side reached a nadir at 12 h after cerebral ischemia, then gradually increased over 24 h to normal reactivity, but TH immunoreactivity between the ischemic side and the contralateral side was no different for up to 12 h after ischemia. The blood concentrations of NA and A were elevated to about twice the control concentration 12 h after ischemia, then gradually decreased back to normal. NPY immunoreactivity of both sides did not change for up to 6 h after ischemia, but NPY immunoreactivity on the lesioned side decreased over 12 h and maintained a plateau. These findings suggest that responses to cerebral ischemia between catecholamines and peptides are varied.
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PMID:Time-dependent changes of vasoactive substances in rat cerebral ischemia. 792 96

The authors conducted an in vivo study, using a rat striatal ischemic model, of the effect of GABAergic transmission upon the dopamine synthesizing enzyme tyrosine hydroxylase in the neurons of the substantia nigra pars compacta. Two hours transient middle cerebral artery occlusion produced massive striatal ischemic damage resulting in a marked decrease of GABAergic projection to the ipsilateral substantia nigra. Histological examinations were conducted in rats killed at three, seven, 15, 30 and 94 days after ischemia. The immunoreactivity for tyrosine hydroxylase in the ipsilateral pars compacta was unaltered up to three days after the ischemic insult, but it was markedly decreased at seven days post-ischemia. At this stage, the number of neurons positive for tyrosine hydroxylase was significantly decreased in the ipsilateral pars compacta, whereas there was no significant reduction in the number of pars compacta neurons containing Nissl substance. By 30 days post-ischemia, the tyrosine hydroxylase-positive cell number in the ipsilateral pars compacta appeared to be equivalent to that of the contralateral side. It was also noted that continuous intraventricular administration of a GABAA receptor agonist muscimol, initiated from 24 h post-ischemia, effectively prevented the transient reduction of immunoreactivity for tyrosine hydroxylase in the ipsilateral pars compacta at seven and 15 days after ischemic insult. The present study revealed that the striatal ischemic lesion induced a transient down-regulation of tyrosine hydroxylase synthesis in the pars compacta neurons, which could be prevented by administration of GABA agonist, suggesting that GABAergic transmission greatly affects dopamine metabolism in these cells.
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PMID:Gabaergic transmission and tyrosine hydroxylase expression in the nigral dopaminergic neurons: an in vivo study using a reversible ischemia model of rats. 880 97

A 10-min period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers a delayed retrograde degeneration of 35-40% of dopaminergic nigrostriatal (NS) neurons. The mechanism of the NS degeneration is believed to involve oxygen radical formation secondary to a postischemic increase in dopamine turnover (monoamine oxidase, MAO). If the oxygen radical increase is sufficiently severe, lipid peroxidative injury to the striatal NS terminals is followed by retrograde degeneration of the NS cell bodies. In the present study, we examined whether the novel brain-penetrating lipid antioxidant pyrrolopyrimidine, U-101033E, and its aromatized analog, U-104067F, could attenuate dopaminergic neurodegeneration in this model. Male Mongolian gerbils were dosed with U-101033E (1.5, 5, or 15 mg/kg, by mouth, twice daily) or U-104067F (5 or 15 mg/kg, by mouth, twice daily) for 27 days beginning on the day of the 10-min ischemic insult. Preservation of NS neurons was assessed by tyrosine hydroxylase immunohistochemistry at 28 days. In vehicle (40% hydroxypropyl-beta-cyclodextrin)-treated animals, there was a 42% loss of NS neurons. In contrast, gerbils that received 5 or 15 mg/kg U-101033E twice daily had only a 23% or 28% loss of NS neurons, respectively (P < 0.002 vs. vehicle). U-104067F showed little effect at sparing neurons at the 10 mg/kg dose, but did significantly attenuate neuronal loss to only 20% at the 30 mg/kg dose (P < 0.01 vs. vehicle). The results show that both the pyrrolopyrimidines (U-101033E and U-104067F) significantly attenuate the postischemic loss of NS dopaminergic neurons and further support the involvement of a dopamine metabolism-derived, oxygen radical-induced lipid peroxidative mechanism.
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PMID:Neuroprotective effects of the novel brain-penetrating pyrrolopyrimidine antioxidants U-101033E and U-104067F against post-ischemic degeneration of nigrostriatal neurons. 908 14

1. Carnosine, anserine, and homocarnosine are endogenous dipeptides concentrated in brain and muscle whose biological functions remain in doubt. 2. We have tested the hypothesis that these compounds function as endogenous protective substances against molecular and cellular damage from free radicals, using two isolated enzyme systems and two models of ischemic brain injury. Carnosine and homocarnosine are both effective in activating brain Na, K-ATPase measured under optimal conditions and in reducing the loss of its activity caused by incubation with hydrogen peroxide. 3. In contrast, all three endogenous dipeptides cause a reduction in the activity of brain tyrosine hydroxylase, an enzyme activated by free radicals. In hippocampal brain slices subjected to ischemia, carnosine increased the time to loss of excitability. 4. In in vivo experiments on rats under experimental hypobaric hypoxia, carnosine increased the time to loss of ability to stand and breath and decreased the time to recovery. 5. These actions are explicable by effects of carnosine and related compounds which neutralize free radicals, particularly hydroxyl radicals. In all experiments the effective concentration of carnosine was comparable to or lower than those found in brain. These observations provide further support for the conclusion that protection against free radical damage is a major role of carnosine, anserine, and homocarnosine.
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PMID:Biochemical and physiological evidence that carnosine is an endogenous neuroprotector against free radicals. 914 Jul 2

The present study describes the effect of hypocapnic ischemia caused by hyperventilation on striatal levels of dopamine, DOPAC, HVA and activity of tyrosine hydroxylase in striatal synaptosomes isolated from the brain of newborn piglets. Hyperventilation did not result in statistically significant changes in the striatal level of dopamine and its major metabolites; however, it was observed that after 20 min of recovery the levels of striatal tissue dopamine, DOPAC and HVA increase by 195%, 110% and 205%, respectively. The level of DOPA (3,4-dihydroxyphenylalanine), which was used as an index of tyrosine hydroxylase activity, also increased after recovery. The rate of dopamine synthesis was 32 pmoles/mg protein/10 min in control piglets and after recovery this increased to 132 pmoles/mg protein/10 min. Measurement of the tyrosine hydroxylase activity in Triton X-100 treated synaptosomes showed that, after 20 min of recovery, there was an increase in Vmax with no change in K(m) for pteridine cofactor, compared to control. This is consistent with the enzyme having been covalently modified (activated) during tissue ischemia caused by hyperventilation and remaining activated well into the recovery period. We postulate that ischemia can induce long lasting alterations in dopamine synthesis, which may play some role in mediation of hypoxic cell injury in immature brain.
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PMID:Activation of tyrosine hydroxylase in striatum of newborn piglets in response to hypocapnic ischemia and recovery. 926 12

Dopaminergic neurons of the substantia nigra pars compacta were examined in the rat brain following striatal infarction subsequent to transient focal cerebral ischemia. Rats had the middle cerebral artery occluded for 2 h or were sham-operated, and tyrosine hydroxylase immunoreactivity was evaluated by Western blot and immunohistochemistry at different times ranging from 1 to 60 days after ischemia. The number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta was counted under the light microscope and compared to that in the contralateral side and controls. No changes of tyrosine hydroxylase immunoreactivity were detected in the ipsilateral versus the contralateral substantia nigra of sham-operated rats or 1 day after ischemia. However, a statistically significant reduction of tyrosine hydroxylase-immunoreactive cells became apparent in the ipsilateral compared with the contralateral substantia nigra at 7 and 14 days after ischemia. This reduction showed a clear recovery at 30 days after ischemia, and no signs of difference between the ipsilateral and the contralateral side were apparent by 60 days. Therefore, the reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra was only transiently seen from 1 to 2 weeks following ischemia. The observed loss of tyrosine hydroxylase was not accompanied by signs of cell death or gliosis in the ipsilateral pars compacta. The present results show a transitory reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra pars compacta after focal ischemia and suggest that striatal infarction causes a transient deficit of dopaminergic function.
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PMID:Striatal infarction in the rat causes a transient reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra. 944 Jan 26

Delta opioid peptide [D-Ala2,D-leu5]enkephalin (DADLE) can prolong organ preservation and increases myocardial tolerance to ischemia. Our study examined the protective property of DADLE against methamphetamine- (METH) induced dopaminergic terminal damage in the central nervous system. Because the neurotoxicity of METH involves reactive oxygen species, we also examined if DADLE might be an antioxidative agent in vitro. DADLE at 2 and 4 mg/kg (i.p.), given 30 min before each METH administration (5 or 10 mg/kg, i.p., four injections in a day at 2-hr intervals), dose-dependently blocked the METH-induced long-term dopamine transporter loss. The opioid antagonist naltrexone blocked this action of DADLE in both aspects of striata but tends not to affect the effects of DADLE in the nucleus accumbens. DADLE did not alter changes in body temperature induced by METH. The reduction of striatal dopaminergic content and tyrosine hydroxylase activity caused by METH, however, were not blocked by DADLE. In vitro, DADLE was approximately equipotent to glutathione in inhibiting both superoxide anion formation induced by xanthine oxidase and hydroxyl radical formation evoked by ferrous/citrate complex. DADLE was only slightly less potent than glutathione in inhibiting the iron/ascorbate-induced brain lipid peroxidation. These results suggest that DADLE can protect the terminal membranes of dopaminergic neurons against METH-induced insult but not the loss of dopaminergic content and tyrosine hydroxylase activity and that this action of DADLE might involve opioid receptors as well as the sequestration of free radical.
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PMID:Delta opioid peptide [D-Ala2,D-leu5]enkephalin blocks the long-term loss of dopamine transporters induced by multiple administrations of methamphetamine: involvement of opioid receptors and reactive oxygen species. 976 53


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