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:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study examined whether thrombin-induced microglial activation could contribute to death of dopaminergic neurons in the rat substantia nigra (SN) in vivo. Seven days after thrombin injection into the SN, tyrosine hydroxylase immunohistochemistry showed a significant loss of nigral dopaminergic neurons. In parallel, thrombin-activated microglia, visualized by immunohistochemical staining using antibodies against the complement receptor type 3 (OX-42) and the major histocompatibility complex class II antigens were also observed in the SN, where degeneration of nigral neurons was found. Reverse transcription PCR at various time points demonstrated that activated microglia in vivo exhibited an early and transient expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and several proinflammatory cytokines, including interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor alpha. Western blot analysis and double-label immunohistochemistry showed an increase in the expression of iNOS and COX-2 and the colocalization of these proteins within microglia. The thrombin-induced loss of SN dopaminergic neurons was partially inhibited by NG-nitro-L-arginine methyl ester hydrochloride, an NOS inhibitor, and by DuP-697, a COX-2 inhibitor. Additional studies demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) were activated in the SN as early as 30 min after thrombin injection, and that these kinases were localized within microglia. Inhibition of ERK1/2 and p38 MAPK reduced iNOS and COX-2 mRNA expression and rescued dopaminergic neurons in the SN. The present results strongly suggest that microglial activation triggered by endogenous compound(s) such as thrombin may be involved in the neuropathological processes of dopaminergic neuronal cell death that occur in Parkinson's disease.
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PMID:Thrombin-induced microglial activation produces degeneration of nigral dopaminergic neurons in vivo. 1284 92

Recovery of erectile dysfunction after cavernous nerve injury takes a long period. To elucidate this mechanism, unilateral cavernous nerve of male rat was cut, and the expression level of a nerve regeneration marker, the growth associated protein-43 (GAP-43) mRNA was evaluated by in situ hybridization and RT-PCR. While GAP-43 mRNA expression was transiently increased in the injured neurons of the major pelvic ganglion (MPG) at 7 days after nerve injury, continuous increase of GAP-43 mRNA was observed in the contralateral MPG from 7 days to 6 months after the nerve injury. Histochemical double-labeling studies for either neuronal NOS (nNOS) or tyrosine hydroxylase (TH) and the GAP-43 mRNA expression demonstrated that in injured MPG the transient up-regulation of GAP-43 mRNA was mainly seen in nNOS negative and/or TH positive neurons, suggesting non-parasympathetic post-ganglionic neurons, and also demonstrated that in contralateral MPG GAP-43 mRNA positive neurons were gradually increased in nNOS positive but TH negative neurons, suggesting parasympathetic post-ganglionic neurons. When a retrograde tracer Fluorogold (FG) was injected into the penile crus 7 days before histological experiments, FG-positive neurons were, if any, hardly seen in nNOS-positive neurons of the injured MPG for at least 6 months, whereas numerous FG-positive cells were seen in nNOS-positive neurons of the contralateral MPG. These results suggest that post-ganglionic projecting neurons of the intact side, which express increased GAP-43 mRNA, would be most likely to contribute to the recovery of the erectile function after unilateral cavernous nerve injury possibly by a plastic change such as nerve sprouting.
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PMID:Cavernous nerve injury elicits GAP-43 mRNA expression but not regeneration of injured pelvic ganglion neurons. 1296 41

We investigated the immunohistochemical alterations of neuronal nitric oxide synthase (nNOS), endothelial NOS (eNOS), tyrosine hydroxylase (TH), microtubule-associated protein 2a,b (MAP 2), glial fibrillary acidic protein (GFAP), parvalbumin (PV), and dopamine transporter (DAT) in the striatum and substantia nigra following the application of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. TH-, MAP 2- and DAT-immunoreactive cells were decreased gradually in the striatum and substantia nigra from 1 day up to 7 days after MPTP treatment, as well as the reduction of the striatal dopamine, DOPAC and HVA content. The number of GFAP-immunoreactive astrocytes increased gradually in the striatum and substantia nigra from 1 day up to 7 days after MPTP treatment. Striatal nNOS-immunoreactive cells were unchanged in MPTP-treated mice. In the substantia nigra, intense immunoreactivity of nNOS-positive cells increased 5 hr after MPTP treatment. Thereafter, the immunoreactivity of nNOS-positive cells decreased gradually from 1 day up to 7 days after MPTP treatment. eNOS-immunopositive cells were unchanged in the striatum and substantia nigra. These results demonstrate that nNOS may play a key role in the development of MPTP neurotoxicity. Our findings also indicate that MPTP can cause the functional damage of interneurons in the substantia nigra, but not in the striatum.
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PMID:Cerebral alterations in a MPTP-mouse model of Parkinson's disease--an immunocytochemical study. 1452 25

This study investigated the nature of vasodilator mechanisms in the dorsal aorta of the giant shovelnose ray, Rhinobatus typus. Anatomical techniques found no evidence for an endothelial nitric oxide synthase, but neural nitric oxide synthase was found to be present in the perivascular nerve fibres of the dorsal aorta and other arteries and veins using both NADPH-diaphorase staining and immunohistochemistry with a specific neural NOS antibody. Arteries and veins both contained large nNOS-positive nerve trunks from which smaller nNOS-positive bundles branched and formed a plexus in the vessel wall. Single, varicose nNOS-positive nerve fibres were present in both arteries and veins. Within the large bundles of both arteries and veins, groups of nNOS-positive cell bodies forming microganglia were observed. Double-labelling immunohistochemistry using an antibody to tyrosine hydroxylase showed that nearly all the NOS nerves were not sympathetic. Acetylcholine always caused constriction of isolated rings of the dorsal aorta and the nitric oxide donor, sodium nitroprusside, did not mediate any dilation. Addition of nicotine (3 x 10(-4) M) to preconstricted rings caused a vasodilation that was not affected by the nitric oxide synthase inhibitor, L-NNA (10(-4) M), nor the soluble guanylyl cyclase inhibitor, ODQ (10(-5) M). This nicotine-mediated vasodilation was, therefore, not due to the synthesis and release of NO. Disruption of the endothelium significantly reduced or eliminated the nicotine-mediated vasodilation. In addition, indomethacin (10(-5) M), an inhibitor of cyclooxygenases, significantly increased the time period to maximal dilation and reduced, but did not completely inhibit the nicotine-mediated vasodilation. These data support the hypothesis that a prostaglandin is released from the vascular endothelium of a batoid ray, as has been described previously in other groups of fishes. The function of the nitrergic innervation of the blood vessels is not known because nitric oxide does not appear to regulate vascular tone.
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PMID:Vasodilator mechanisms in the dorsal aorta of the giant shovelnose ray, Rhinobatus typus (Rajiformes; Rhinobatidae). 1472 May 87

We recently reported that neuronal nitric oxide synthase (nNOS) inhibitor, 7-nitroindazole, can protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. It protected against both dopamine depletions and tyrosine hydroxylase (TH) positive neuron decreases in the mouse brain. In the present study, we further examined whether 7-nitroindazole can also protect against the alterations of TH-, microtubule-associated protein 2a,b (MAP2)-, glial fibrillary acidic protein (GFAP)-, parvalbumin (PV)-, dopamine transporter (DAT)-, nNOS- or endothelial NOS (eNOS)-positive cells, in comparison with pargyline as a relatively selective inhibitor of the monoamine oxidase-B (MAO-B). The present study showed that nNOS inhibitor as well as MAO-B inhibitor has a dose-dependent protective effect against MPTP-induced striatal dopamine and DOPAC depletion in mice. Furthermore, the present study revealed that 7-nitroindazole and pargyline can protect the alterations of immunohistochemical changes in the striatum and substantia nigra after MPTP treatment. These protective effects may be, at least in part, produced by the reduction of neuronally derived NO and peroxynitrite caused by MPTP. Our results also demonstrate that MPTP can cause functional damage of interneurons in the substantia nigra. These results suggest the possibility that nNOS inhibitors as well as MAO-B inhibitors may be therapeutically useful in neurodegenerative diseases such as Parkinson's disease. Thus our present results provide valuable information for the pathogenesis of degeneration of the nigrostriatal dopaminergic neuronal pathway.
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PMID:Protective effects of neuronal nitric oxide synthase inhibitor in mouse brain against MPTP neurotoxicity: an immunohistological study. 1501 24

CAD cells are a murine CNS catecholaminergic (tyrosine hydroxylase-positive; TH+) neuronal cell line that undergoes morphological differentiation to resemble CNS catecholaminergic neurons upon serum deprivation. We show here that CAD cells also express neuronal nitric oxide synthase (nNOS) mRNA and protein and produce readily measurable levels of NO. Since both NO and catecholamines (L-DOPA; dopamine; norepinephrine) are redox active molecules, their production within the same cell may affect the cell's vulnerability to insult. Thus, we examined the regulation of NO production by CAD cells and the effect of NO on cell survival. NO is generated in a dose-dependent fashion by treatment with agents (ionomycin; A23817; KCl) known to increase calcium entry across the cell membrane. The NO level can be increased further by pretreatment with sepiapterin, a membrane permeable precursor for BH4 synthesis, suggesting that the BH4 levels or access required for nNOS activation is limited in CAD cells. Reducing mitochondrial Ca2+ uptake using ruthenium red (RuR) increased ionomycin-mediated NO production over ionomycin alone and indicates a critical role for mitochondria in nNOS regulation. Cell death was significantly increased by ionomycin treatment alone or in conjunction with reduced mitochondrial Ca2+ uptake. However, NO was not the primary mediator of cell death since NOS inhibitors rescued only less than 10% of the cells. These data suggest that endogenous NO production by nNOS is not a major factor in CAD cell death under these conditions.
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PMID:Nitric oxide production and regulation of neuronal NOS in tyrosine hydroxylase containing neurons. 1524 34

The present study was undertaken to explore involvement of nitric oxide (NO) in the experimental models of Parkinson's disease. Neurodegeneration was induced by unilateral injections of 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) in the right striatum. Lesions were functionally evaluated by amphetamine-induced asymmetrical behaviour and by decrease in the tyrosine hydroxylase (TH) immunostaining. An induction in the expression of iNOS and augmentation in nitrite content was observed in both the models. The extent of increase in iNOS expression was, however, different but the elevation in the nitrite content was comparable in both the models. The increase in iNOS expression inversely correlated with the tyrosine hydroxylase (TH) immunolabeling. Animals pretreated with a NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), exhibited complete protection against amphetamine induced rotations in both the models. Thus, augmented NO availability subsequent to iNOS induction seems to play an important role in the initial phase of neurodegeneration.
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PMID:Involvement of nitric oxide in neurodegeneration: a study on the experimental models of Parkinson's disease. 1594 31

Neural signaling by melanin-concentrating hormone and its receptor (SLC-1) has been implicated in the control of energy balance, but due to the wide distribution of melanin-concentrating hormone-containing fibers throughout the neuraxis, its critical sites of action for a particular effect have not been identified. The present study aimed to anatomically and functionally characterize melanin-concentrating hormone innervation of the rat caudal brainstem, as this brain area plays an important role in the neural control of ingestive behavior and autonomic outflow. Using retrograde tracing we demonstrate that a significant proportion (5-15%) of primarily perifornical and far-lateral hypothalamic melanin-concentrating hormone neurons projects to the dorsal vagal complex. In the caudal brainstem, melanin-concentrating hormone-ir axon profiles are distributed densely in most areas including the nucleus of the solitary tract, dorsal motor nucleus of the vagus, and sympathetic premotor areas in the ventral medulla. Close anatomical appositions can be demonstrated between melanin-concentrating hormone-ir axon profiles and tyrosine hydroxylase, GABA, GLP-1, NOS-expressing, and nucleus of the solitary tract neurons activated by gastric nutrient infusion. In medulla slice preparations, bath application of melanin-concentrating hormone inhibited in a concentration-dependent manner the amplitude of excitatory postsynaptic currents evoked by solitary tract stimulation via a pre-synaptic mechanism. Fourth ventricular administration of melanin-concentrating hormone (10 microg) in freely moving rats decreased core body temperature but did not change locomotor activity and food and water intake. We conclude that the rich hypothalamo-medullary melanin-concentrating hormone projections in the rat are mainly inhibitory to nucleus of the solitary tract neurons, but are not involved in the control of food intake. Projections to ventral medullary sites may play a role in the inhibitory effect of melanin-concentrating hormone on energy expenditure.
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PMID:Melanin concentrating hormone innervation of caudal brainstem areas involved in gastrointestinal functions and energy balance. 1611 19

By means of double immunohistofluorescence techniques, we have investigated the colocalization of nitric oxide synthase and tyrosine hydroxylase (TH) or serotonin (5-HT) in the central nervous system of the anurans Rana perezi and Xenopus laevis and the urodele Pleurodeles waltl. A wide codistribution of neuronal populations, expressing these markers, was found throughout the brain and spinal cord. In contrast, colocalization of these markers was rather restricted. Only in the caudal portion of the brainstem raphe column in anurans, approximately 80% of the 5-HT-positive cells were also NOS-immunoreactive, whereas in the urodele brain, about 40% of the serotonergic cells at the level of the glossopharyngeal motor nucleus were simultaneously NOS-positive. In various brain regions, a wide codistribution of NOS- and TH-containing neurons was observed, but real colocalization of nitrergic and catecholaminergic cells was only found in a small neuron population in the posterior tubercle of anuran amphibians. Therefore, in amphibians, only a distinct and small cell population within the serotonergic raphe column (anurans and urodele) and in the catecholaminergic posterior tubercle (anurans) seem to produce simultaneously nitric oxide.
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PMID:Colocalization of nitric oxide synthase and monoamines in neurons of the amphibian brain. 1614 49

Several pharmacological and physiological studies have suggested that GABA(A) receptors (GABA(A) Rs) may exist in the rat major pelvic ganglion (MPG), a large coalescent pelvic ganglion that contains both sympathetic and parasympathetic components which innervates pelvic organs. However, the presence of GABA(A) R in the MPG has never been demonstrated directly by morphological studies. In the present study, we used immunohistochemistry to demonstrate the existence of GABA(A) R beta2/3 subunits for the first time in the rat MPG. We also analyzed the neurochemical properties of MPG neurons expressing GABA(A) R beta2/3 subunits. GABA(A) R beta2/3-immunoreactive (-IR) neurons occupied 27.4+/-7.0% of the whole neuronal population, and many of these (77.6%) were co-localized with tyrosine hydroxylase (TH). Likewise, most (86.5%) of TH-IR neurons were GABA(A) R beta2/3-positive. GABA(A) R beta2/3 subunits were also expressed in a few VIP- or NOS-IR neurons, the cholinergic or non-adrenergic, non-cholinergic (NANC) neurons. These results suggest that GABA(A) Rs are involved in the modulation of most sympathetic, noradrenergic neurons and also a subset of VIP and NOS neurons of the rat MPG.
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PMID:Expression of GABAA receptor beta2/3 subunits in the rat major pelvic ganglion. 1671 6


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