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)

Oxidative stress, reactive oxygen (ROS), and nitrogen (RNS) species have been known to be involved in a multitude of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Both ROS and RNS have very short half-lives, thereby making their identification very difficult as a specific cause of neurodegeneration. Recently, we have developed a high performance liquid chromatography/electrochemical detection (HPLC/EC) method to identify 3-nitrotyrosine (3-NT), an in vitro and in vivo biomarker of peroxynitrite production, in cell cultures and brain to evaluate if an agent-driven neurotoxicity is produced by the generation of peroxynitrite. We show that a single or multiple injections of methamphetamine (METH) produced a significant increase in the formation of 3-NT in the striatum. This formation of 3-NT correlated with the striatal dopamine depletion caused by METH administration. We also show that PC12 cells treated with METH has significantly increased formation of 3-NT and dopamine depletion. Furthermore, we report that pretreatment with antioxidants such as selenium and melatonin can completely protect against the formation of 3-NT and depletion of striatal dopamine. We also report that pretreatment with peroxynitrite decomposition catalysts such as 5, 10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron III (FeTMPyP) and 5, 10, 15, 20-tetrakis (2,4,6-trimethyl-3,5-sulfonatophenyl) porphinato iron III (FETPPS) significantly protect against METH-induced 3-NT formation and striatal dopamine depletion. We used two different approaches, pharmacological manipulation and transgenic animal models, in order to further investigate the role of peroxynitrite. We show that a selective neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole (7-NI), significantly protect against the formation of 3-NT as well as striatal dopamine depletion. Similar results were observed with nNOS knockout and copper zinc superoxide dismutase (CuZnSOD)-overexpressed transgenic mice models. Finally, using the protein data bank crystal structure of tyrosine hydroxylase, we postulate the possible nitration of specific tyrosine moiety in the enzyme that can be responsible for dopaminergic neurotoxicity. Together, these data clearly support the hypothesis that the reactive nitrogen species, peroxynitrite, plays a major role in METH-induced dopaminergic neurotoxicity and that selective antioxidants and peroxynitrite decomposition catalysts can protect against METH-induced neurotoxicity. These antioxidants and decomposition catalysts may have therapeutic potential in the treatment of psychostimulant addictions.
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PMID:Methamphetamine-induced dopaminergic neurotoxicity: role of peroxynitrite and neuroprotective role of antioxidants and peroxynitrite decomposition catalysts. 1146 92

The aim of this investigation was to assess whether in teleosts, as in mammals, nitric oxide (NO) is involved in the regulation of cellular activity in the adrenal homolog. Larval and juvenile stages of the rainbow trout, Oncorhynchus mykiss, were used, in which the adrenal homolog consists of chromaffin adrenergic and interrenal steroidogenic cells localized mainly in the head kidney where there are also ganglion cells and nerve fibres that innervate the gland. In 12-month-old juveniles, the immunohistochemical reaction for neuronal nitric oxide synthase (nNOS), which catalyzes the synthesis of NO, revealed the presence of this enzyme in some nerve fibres and ganglion cells and only rarely in chromaffin cells. The latter are identified by the immunohistochemical reaction for tyrosine hydroxylase (TH) and phenylethanolamine-N-methyltransferase (PNMT). In larvae at 27 days postfertilization, numerous cells dispersed in the head kidney are nNOS positive, whereas the TH and PNMT positive cells are very rare. At hatching (31 days postfertilization), the positivity for nNOS in the cells of the head kidney disappears and reappears at 60 days posthatching in some nerve cells and fibres. These results suggest an involvement of NO in the regulation of adrenal function as in mammals and the nature of nNOS positive cells present in the head kidney of larvae of 27 days is discussed.
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PMID:Immunohistochemical localization of nNOS in the head kidney of larval and juvenile rainbow trout, Oncorhynchus mykiss. 1170 68

Nerve fibres play an important role in the regulation of gastric emptying. The aims of this study were to clarify the distribution, projections and origin of neuronal type nitric oxide synthase (NOS)-, tyrosine hydroxylase (TH)-, vesicular acetylcholine transporter (VAchT)- and peptide-containing nerve fibres of the rat pyloric sphincter. Extrinsic and local denervations of the sphincter were performed in order to reveal the origin and projections of the various nerve fibre populations. Pylorus from control and denervated animals were processed for the immunocytochemical demonstration of cholecystokinin (CCK), enkephalin, gastrin-releasing peptide (GRP), somatostatin, calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), pituitary adenylate cyclase-activating peptide (PACAP), substance P (SP), vasoactive intestinal peptide (VIP), galanin, NOS, VAchT and TH. VAchT, TH, nNOS, and all of the peptides investigated were found in nerve fibres innervating the pyloric sphincter, and coexistence of several putative neurotransmitters were revealed. Extrinsic denervation caused a total loss of NPY/TH-, SP/CGRP- and SP/CGRP/VIP/NOS/PACAP-containing nerve fibres. Local denervation immediately proximal to the sphincter markedly reduced the numbers of VIP/NOS/galanin- and VIP/NOS/galanin/PACAP +/- NPY-containing fibres within the sphincter suggesting an origin of these fibres in myenteric ganglia in the antral region; denervation at the level of the oxyntic-pyloric border had no effect. Local denervation immediately distal to the sphincter caused a marked decrease in VAchT-, SP/enkephalin-, enkephalin-, somatostatin-, CCK- and GRP-containing fibres within the sphincter suggesting that these emanate from the duodenum. The latter procedure also reduced the number of SP/CGRP-containing fibres of extrinsic origin within the pyloric sphincter.
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PMID:Origins and projections of nerve fibres in rat pyloric sphincter. 1213 47

The reinnervation process is crucial for the survival and functioning of cell, tissue or organ transplants. This study was designed to examine the exact time of reinnervation of intraocular pancreatic tissue transplants in rats. The rate of survival of neuropeptide-containing cells in pancreatic tissue grafts was also investigated. Calcitonin gene-related peptide (CGRP), galanin (GAL), neuropeptide Y (NPY) were observed in the surviving nerve cell bodies of the grafts. The iridal nerves reinnervating the pancreatic grafts expressed CGRP, GAL, NPY and choline-acetyl-transferase (ChAT) on day 5, and tyrosine hydroxylase (TH) and nitric oxide synthase (bNOS) on day 6 of the transplantation period. The expression of CGRP in the reinnervating nerves was more consistent when compared to GAL, NPY, ChAT, TH and bNOS. Although all of the three neuropeptides (CGRP, GAL, NPY) were present in the surviving nerve cell bodies of the pancreatic tissue graft up to the end (day 9) of the transplantation period, the number of CGRP-immunopositive cells was consistently higher throughout the transplantation period. Hence, the number of CGRP-positive cells in the pancreatic tissue graft was significantly (P < 0.05) higher than that of GAL and NPY. In conclusion, pancreatic fragments were reinnervated by neuropeptidergic (CGRP, NPY) and cholinergic (ChAT) nerves within the first 5 days of transplantation. In addition to the reinnervation of pancreatic tissue grafts, the intrinsic neurones of the grafts also survived after transplantation. The rate of survival of CGRP-containing cells in the pancreatic tissue grafts was more consistent compared to that of NPY and GAL.
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PMID:Pancreatic tissue grafts are reinnervated by neuro-peptidergic and cholinergic nerves within five days of transplantation. 1218 68

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway injury similar to that observed in Parkinson's disease. Many hypotheses have been proposed to explain the mechanisms underlying MPTP neurotoxicity. Previous work showed that the inhibitor of neuronal nitric oxide synthase (nNOS) might produce protection against MPTP-induced dopaminergic toxicity. To exactly test the role of NO in MPTP neurotoxicity, we examined the effect of nNOS inhibitor 7-nitroindazole, in comparison with that of nonselective NOS inhibitor (L-NAME), immunosuppressant (FK-506), monoamine oxidase (MAO) inhibitors (clorgyline and pargyline), N-methyl-D-aspartate receptor antagonist (MK-801) and Ca2+ antagonist (amlodipine). Among seven compounds, 7-nitroindazole produced dose-dependent protection against MPTP-induced depletion of striatal dopamine and its metabolite 3,4-dihydroxyphenyl acetic acid (DOPAC) in mice. Clorgyline and pargyline also showed a significant effect on MPTP-induced dopamine depletion in the mouse striatum. However, both compounds did not protect against MPTP-induced depletion of striatal DOPAC Our immunohistological study with tyrosine hydroxylase (TH) and microtuble-associated protein 2 (MAP 2) showed that 7-nitroindazole or pargyline can protect against MPTP-induced depletion of TH and MAP 2 immunostained neurons in the substantia nigra. Furthermore, these compounds reduced a marked increase in GFAP-positive astrocytes of the mouse striatum after MPTP treatments. The present study demonstrates that nNOS inhibitor 7-nitroindazole as well as MAO inhibitors clorgyline and pargyline can produce dose-dependent neuroprotection against the dopaminergic neurotoxicity of MPTP. However, nonselective NOS inhibitor L-NAME, immunosuppressant FK-506, NMDA receptor antagonist MK-801 and Ca2+ antagonist amlodipine did not show a beneficial effect on MPTP neurotoxicity.
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PMID:Role of nitric oxide synthase against MPTP neurotoxicity in mice. 1239 1

In the mammalian neocortex, neurons containing tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, constitute an enigmatic and ill-defined group of aspiny non-pyramidal cells. In the human neocortex, these neurons are mostly found in layers V-VI, the same layers in which another conspicuous group of nitrergic non-pyramidal cells are found - those containing nitric oxide synthase (nNOS) and that can be labeled by nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) histochemistry. The main aim of the present study was to determine the extent to which neurons and fibers containing TH, NADPHd or nNOS co-localize in the human temporal cortex, using immunocytochemistry and NADPHd histochemistry. Furthermore, we have quantified the degree to which axons immunoreactive (ir) for TH contact the somata of neurons by co-labeling with the neuron-specific nuclear protein NeuN. As a result, we show that the population of TH-ir neurons can be subdivided into two main neurochemical groups: those expressing nNOS (26%) and those that do not (74%). There was no co-localization of TH with nNOS in the prominent horizontally oriented plexus of fibers in layer I and we did not observe any double bouquet cells, chandelier cells or basket cells that contained TH. Finally, we observed that only 6% of the TH-ir axonal boutons examined (n = 1724) could be seen to contact neuronal somata. Thus, most TH-ir axons must form synapses with dendrites. In conjunction with data from previous studies, these results suggest that TH is found in different neurochemically defined subpopulations of non-pyramidal neurons in layers V-VI of the human temporal cortex. Consequently, it appears that a partial overlap of the catecholaminergic and nitrergic systems is probably due to the intrinsic cortical TH-nNOS-ir neurons.
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PMID:Different populations of tyrosine-hydroxylase-immunoreactive neurons defined by differential expression of nitric oxide synthase in the human temporal cortex. 1257 Nov 19

Nitric oxide (NO) is known to regulate the release of arginine-vasopressin (AVP) and oxytocin (OT) by the paraventricular nucleus (PVN) and the supraoptic nucleus (SON). The aim of the current study was to identify in these nuclei the NO-producing neurons and the NO-receptive cells in mice. The determination of NO-synthesizing neurons was performed by double immunohistochemistry for the neuronal form of NO synthase (NOS), and AVP or OT. Besides, we visualized the NO-receptive cells by detecting cyclic GMP (cGMP), the major second messenger for NO, by immunohistochemistry on hypothalamus slices. Neuronal NOS was exclusively colocalized with OT in the PVN and the SON, suggesting that NO is mainly synthesized by oxytocinergic neurons in mice. By contrast, cGMP was not observed in magnocellular neurons, but in GABA-, tyrosine hydroxylase- and glutamate-positive fibers, as well as in GFAP-stained cells. The cGMP-immunostaining was abolished by incubating brain slices with a NOS inhibitor (L-NAME). Consequently, we provide the first evidence that NO could regulate the release of AVP and OT indirectly by modulating the activity of the main afferents to magnocellular neurons rather than by acting directly on magnocellular neurons. Moreover, both the NADPH-diaphorase activity and the mean intensity of cGMP-immunofluorescence were increased in monoamine oxidase A knock-out mice (Tg8) compared to control mice (C3H) in both nuclei. This suggests that monoamines could enhance the production of NO, contributing by this way to the fine regulation of AVP and OT release and synthesis.
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PMID:The effects of nitric oxide on magnocellular neurons could involve multiple indirect cyclic GMP-dependent pathways. 1258 Nov 64

The prenatal and postnatal development of NADPH-diaphorase (NADPH-d)/neuronal nitric oxide synthase (nNOS) positive neurons was studied in the striatum of rats. NADPH-d was demonstrated enzyme histochemically and nNOS immunohistochemically using a polyclonal antibody. NADPH-d neurons appeared in the ventrolateral part of the striatum on embryonic day 18 (E18). Thereafter, the number of NADPH-d neurons increased and began to distribute homogeneously in the striatum. The density of NADPH-d neurons became highest at postnatal day 5 (P5) and then decreased as the volume of the striatum continued to increase. The number of NADPH-d neurons reached its peak around 3-4 weeks after birth. The sizes of NADPH-d neurons were measured. The NADPH-d neurons grew larger until P14 (mean area 260 microm(2)) and became smaller thereafter (mean area 170 microm(2)). Patches of high NADPH-d activity and tyrosine hydroxylase (TH) immunoreactivity were also examined in the developing striatum. The distributions of NADPH-d patches overlapped with those of TH-immunoreactive patches by P10. The spatiotemporal appearance of nNOS and overlapping of nNOS patchy distribution with TH point to an important role of NO and to an interaction between nNOS and DA fibers during development of the striatum.
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PMID:Developing patterns of nitric oxide synthesizing neurons in the rat striatum: histochemical analysis. 1264 52

Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output pathways are still awaited. Therefore, we performed quantitative choline acetyltransferase (ChAT) immunocytochemistry to localize major cholinergic nuclei and to determine the number of respective cholinergic neurons in the rabbit forebrain. The density of ChAT-immunoreactive terminals in layer V of distinct neocortical territories and in hippocampal subfields was also measured. Another cholinergic marker, the low-affinity neurotrophin receptor (p75(NTR)), was also employed to identify subsets of cholinergic neurons. Double-immunofluorescence labeling of ChAT and p75(NTR), calbindin D-28k (CB), parvalbumin, calretinin, neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase, or substance P was used to elucidate the neuroanatomical borders of cholinergic nuclei and to analyze the neurochemical complexity of cholinergic cell populations. Cholinergic projection neurons with heterogeneous densities were found in the medial septum, vertical and horizontal diagonal bands of Broca, ventral pallidum, and magnocellular nucleus basalis (MBN)/substantia innominata (SI) complex; cholinergic interneurons were observed in the caudate nucleus, putamen, accumbens nucleus, and olfactory tubercule, whereas the globus pallidus was devoid of cholinergic nerve cells. Cholinergic interneurons were frequently present in the hippocampus and to a lesser extent in cerebral cortex. Cholinergic projection neurons, except those localized in SI, abundantly expressed p75(NTR), and a subset of cholinergic neurons in posterior MBN was immunoreactive for CB and nNOS. A strict laminar distribution pattern of cholinergic terminals was recorded both in the cerebral cortex and in CA1-CA3 and dentate gyrus of the hippocampus. In summary, the structural organization and chemoarchitecture of rabbit basal forebrain may be considered as a transition between that of rodents and that of primates.
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PMID:Rabbit forebrain cholinergic system: morphological characterization of nuclei and distribution of cholinergic terminals in the cerebral cortex and hippocampus. 1271 17

Gill and air sac of the Indian catfish Heteropneustes fossilis harbour a nerve network comprising an innervated system of neuroepithelial endocrine cells; the latter cells are found especially in the gill. A series of antibodies was used for the immunohistochemical detection of neurotransmitters of the neural non-adrenergic, non-cholinergic (NANC) systems such as the sensory neuropeptides (enkephalins), the inhibitory neuropeptide VIP and neuronal nitric oxide synthase (nNOS) responsible for nitric oxide (NO) production which is an inhibitory NANC neurotransmitter. NADPH-diaphorase (NADPH-d) histochemistry was used as marker of nNOS although it is not a specific indicator of constitutively-expressed NOS in gill and air sac tissues. A tyrosine hydroxylase antibody was used to investigate adrenergic innervation. Nitrergic and VIP-positive sensory innervation was found to be shared by gill and air sac. Immunohistochemistry revealed the presence of enkephalins, VIP, NOS and NADPH-d in nerves associated with branchial and air sac vasculature, and in the neuroendocrine cell systems of the gill. Adrenergic nerve fibers were found in some parts of the air sac vasculature. The origin of the nerve fibers remains unclear despite previous findings showing the presence of both NADPH-d and nNOS in the sensory system of the glossopharyngeal and vagus nerves including the branchial structure. Scarce faintly stained nNOS-positive neurons were located in the gill but were never detected in the air sac. These findings lead to the conclusion that a postganglionic innervation of the airways is absent. Mucous goblet cells in the gill were found to express nNOS and those located in the non-respiratory interlamellar areas of the air sac were densely innervated by nNOS-positive and VIP-positive nerve fibers. Our immunohistochemical studies demonstrate that most arteries of the gill and air sac share a NANC (basically nitrergic) innervation which strongly suggests that they are homologous structures.
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PMID:NANC nerves in the respiratory air sac and branchial vasculature of the Indian catfish, Heteropneustes fossilis. 1283 Nov 67


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