UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebellar long-term depression (LTD) is a model system of information storage in which a persistent attenuation of the parallel fiber-Purkinje neuron (PN) synapse is induced by conjunctive stimulation of parallel fiber and climbing fiber inputs at low frequency. As some studies have suggested that release of the gaseous second messenger, nitric oxide (NO), in the molecular layer and the consequent activation of soluble guanylate cyclase and cGMP-dependent protein kinase (PKG) in the PN, is necessary for LTD induction, we have further examined this hypothesis using a cell culture protocol. In cerebellar cultures made from transgenic mice in which the gene for neuronal nitric oxide synthase (nNOS) has been rendered null, LTD induced by glutamate/depolarization conjunctive stimulation was indistinguishable from that in cultures from wild-type mice in terms of amplitude, rate of onset, and duration. Bath application of cGMP analogs produced a large (80%), transient attenuation of glutamate-gated inward currents. However, application of an activator of soluble guanylate cyclase or an inhibitor of type V cGMP-phosphodiesterase did not mimic the effect of cGMP analogs, and inclusion of cGMP analogs in the patch pipette did not give rise to a slowly developing attenuation, suggesting that these compounds exert their effects at the cell surface. Free Ca was measured in the distal dendritic arbor of single PNs by fura-2 microfluorimetry.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An evaluation of the nitric oxide/cGMP/cGMP-dependent protein kinase cascade in the induction of cerebellar long-term depression in culture. 762 38

Hypoxia-ischemia damages selected regions of the immature at different ages. Prior to 32 weeks gestation the periventricular white matter is selectively vulnerable but in the last trimester the basal ganglia become especially vulnerable to injury. Hypoxia-ischemia causes injury by activating a series of biochemical events that unfolds over a period of hours to days following the initial insult and we are investigating the ways in which age modifies these events. The cascade includes release of glutamate, overstimulation of excitatory amino acid receptors and raised intracellular levels of calcium. Clinically this series is manifested by hypoxic-ischemic encephalopathy (HIE), a syndrome that includes coma, seizures, a burst suppression EEG, respiratory depression and severe hypotonia. Clinical studies have established a relationship between the severity of neonatal encephalopathy and later manifestations of brain damage or cerebral palsy. Potential neuroprotective therapies need to be effective when given after the insult but the 'therapeutic time window' for most N-methyl-D-aspartate (NMDA) glutamate antagonists is limited after injury. Using a model of hypoxic-ischemic injury and neonatal rats and hypothermic-circulatory arrest in dogs, we found that immunohistochemical staining for neuronal nitric oxide synthase (nNOS) is markedly increased from 6 to 24 h after the insult in the basal ganglia and cortex. The induction of nNOS preceded the time of maximal neuronal necrosis and during the time when many apoptotic nuclei were appearing. We have also found that a brief period of 2 h of mild hypothermia (32 degrees C) following hypoxia-ischemia in neonatal rats delayed neuronal necrosis by more than a week. We are determining whether this delay is related to a change in nNOS activation. Induction of nNOS in the post-insult period may contribute to expression of injury and signs of encephalopathy following a hypoxic-ischemic insult.
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PMID:Hypoxic and ischemic disorders of infants and children. Lecture for 38th meeting of Japanese Society of Child Neurology, Tokyo, Japan, July 1996. 918 71

We examined the effects of potent neuronal nitric oxide synthase inhibitors, 3-bromo-7-nitro indazole (3-Br-7-NI) and S-methyl-L-thiocitrulline (S-Me-TC) on general behaviour, vigilance stages and electroencephalographic (EEG) power spectra in rats. In addition, we studied the effect of 7-nitro indazole (7-NI) on EEG power spectra in rats during dark and light periods. 3-Br-7-NI induced ptosis and decrease of slow wave sleep and rapid eye movement sleep in the rat. 7-NI and 3-Br-7-NI reduced the EEG power density in all frequency bands in the rat, suggesting a depression of central neuronal activity. This effect of 7-NI was more prominent during the day than during the night, indicating a circadian variation in the nitric oxide synthase (NOS) response to NOS inhibitor. EEG power was the most reduced in the 7-9 Hz range of the rhythmic slow activity (theta rhythm), which is in accordance with decreased locomotion observed following administration of NOS inhibitors. Although S-Me-TC is the most potent NOS inhibitor in vitro experiments, it had less effect on vigilance and EEG power in the rat than other NOS inhibitors used in this study, probably due to its short lasting and blood pressure raising effect. The present results indicate that nitric oxide exerts an excitatory and circadian dependent effect in the central neuronal structures involved in the regulation of vigilance.
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PMID:Vigilance and EEG power in rats: effects of potent inhibitors of the neuronal nitric oxide synthase. 922 90

The different cell types comprising cardiac muscle express one or more of the three isoforms (neuronal NOS, or nNOS; inducible NOS, or iNOS; and endothelial NOS, or eNOS) of nitric oxide synthase (NOS). nNOS is expressed in orthosympathetic nerve terminals and regulates the release of catecholamines in the heart. eNOS constitutively expressed in endothelial cells inhibits contractile tone and the proliferation of underlying vascular smooth muscle cells, inhibits platelet aggregation and monocyte adhesion, promotes diastolic relaxation, and decreases O2 consumption in cardiac muscle through paracrinally produced NO. eNOS is also constitutively expressed in cardiac myocytes from rodent and human species, where it autocrinally opposes the inotropic action of catecholamines after muscarinic cholinergic and beta-adrenergic receptor stimulation. iNOS gene transcription and protein expression are induced in all cell types after exposure to a variety of inflammatory cytokines. Aside from participating in the immune defense against intracellular microorganisms and viruses, the large amounts of NO produced autocrinally or paracrinally mediate the vasoplegia and myocardial depression characteristic of systemic immune stimulation and promote cell death through apoptosis. In cardiac myocytes, NO may regulate L-type calcium current and contraction through activation of cGMP-dependent protein kinase and cGMP-modulated phosphodiesterases. Other mechanisms independent of cGMP elevations may operate through interaction of NO with heme proteins, non-heme iron, or free thiol residues on target signaling proteins, enzymes, or ion channels. Given the multiplicity of NOS isoforms expressed in cardiac muscle and of the potential molecular targets for the NO produced, tight molecular regulation of NOS expression and activity at the transcriptional and posttranscriptional level appear to be needed to coordinate the many roles of NO in heart function in health and disease.
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PMID:Nitric oxide synthases and cardiac muscle. Autocrine and paracrine influences. 935 45

Nitric oxide (NO) is one of many vasoactive substances released, from a variety of cells, under conditions of endotoxaemia and sepsis. Under physiological conditions it is produced by two constitutive calcium-dependent enzymes (nitric oxide synthase; NOS) in neurones (nNOS) and endothelial cells (eNOS) and has functions ranging from neurotransmission and vasodilatation to inhibition of platelet adhesion and aggregation. Following bacterial infection, especially with Gram-negative organisms, its formation from L-arginine is enhanced due to the cytokine-mediated induction of a NOS enzyme (iNOS) in cells (e.g. cardiac myocytes, vascular smooth muscle) that do not normally have the ability to synthesize NO. The result of this excessive NO production is enhanced bacterial lysis by activated macrophages, vasoplegia and myocardial depression. These cardiovascular effects can be alleviated by inhibitors of the L-arginine NO pathway, which results in elevated perfusion pressure, restored responsiveness to sympathetic nerve stimulation and to exogenous catecholamines, and to enhanced (endothelin-dependent) myocardial contractility. In patients in shock this approach also leads to detrimental effects (increased systemic vascular resistance, elevated pulmonary artery pressure, reduced cardiac output and oxygen delivery, increased platelet accumulation) and survival is not improved. Because some of these detrimental effects are due to inhibition of eNOS, attempts have been made to examine the effects of substances with a higher selectivity for the induced form of the enzyme. In experimental animals, one of these (L-canavanine) protects endothelial cells from damage, increases survival time and restores vascular responsiveness without increasing blood pressure or peripheral vascular resistance. However, whether even this approach will be of benefit to patients with sepsis remains in doubt since studies in iNOS knock-out mice do not support the concept that eliminating this particular source of NO improves ultimate survival.
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PMID:Nitric oxide in sepsis and endotoxaemia. 951 Oct 84

Nitric oxide (NO) plays a complex role in the pathophysiology of cerebral ischemia. In this study, mutant mice with disrupted type I (neuronal) NO synthase (nNOS) were compared with wild-type littermates after permanent focal ischemia. Cerebral blood flow in the central and peripheral zones of the ischemic distribution were measured with laser doppler flowmetry. Simultaneously, microdialysis electrodes were used to measure extracellular amino acid concentrations and DC potential in these same locations. Blood flow was reduced to <25 and 60% of baseline levels in the central and peripheral zones, respectively; there were no differences in nNOS mutants versus wild-type mice. Within the central ischemic zone, DC potentials rapidly shifted to -20 mV in all mice. In the ischemic periphery, spreading depression (SD)-like waves of depolarization were observed. SD-like events were significantly fewer in the nNOS mutant mice. Concurrent with these hemodynamic and electrophysiological perturbations, extracellular elevations in amino acids occurred after ischemia. There were no detectable differences between wild-type and mutant mice in the ischemic periphery. However, in the central zone of ischemia, elevations in glutamate and GABA were significantly lower in the nNOS mutants. Twenty-four hour infarct volumes in the nNOS mutant mice were significantly smaller than in their wild-type littermates. Overall, the number of SD-like depolarizations and the integrated efflux of glutamate were significantly correlated with infarct size. These results suggest that NO derived from the nNOS isoform contributes to tissue damage after focal ischemia by amplifying excitotoxic amino acid release in the core and deleterious waves of SD-like depolarizations in the periphery.
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PMID:Attenuated neurotransmitter release and spreading depression-like depolarizations after focal ischemia in mutant mice with disrupted type I nitric oxide synthase gene. 980 93

Nitric oxide is formed in the brain primarily by neurons containing neuronal nitric oxide synthase (nNOS), though some neurons may express endothelial NOS (eNOS), and inducible NOS (iNOS) only occurs in neurons following toxic stimuli. Mice with targeted disruption of nNOS (nNOS-) display distended stomachs with hypertrophied pyloric sphincters reflecting loss of nNOS in myenteric plexus neurons. nNOS- animals resist brain damage following middle cerebral artery occlusions consistent with evidence that excess release of nitric oxide mediates neurotoxicity in ischemic stroke. Neuronal NOS- mice have no grossly evident defects in locomotor activity, breeding long-term depression in the cerebellum, long-term potentiation in the hippocampus, and overall sensorimotor function. However, nNOS- animals display excessive, inappropriate sexual behavior and dramatic increases in aggression. Because the cerebellum possesses the greatest levels of nNOS neurons in the brain, it was surprising that presumed cerebellar functions such as balance and coordination were grossly normal in nNOS- mice. These previous studies were all conducted during the day (between 1400 and 1600, lights on at 0700). We now report striking, discrete abnormalities in balance and motor coordination in nNOS-mice reflected selectively at night.
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PMID:Nocturnal motor coordination deficits in neuronal nitric oxide synthase knock-out mice. 1007 13

Nitric oxide synthase (NOS) and the nicotinic acetylcholine receptor (nAChR) immunoreactivity of the cerebral cortex was studied in adult Macaca fascicularis monkeys at light- and electron microscopic levels. NOS was located by means of the polyclonal antibodies developed by Transduction Laboratories (Lexington, KY, USA), as primary serum, in a dilution of 1:1000, and nAChR was located by means of biotinylated alpha-bungarotoxin (BTX) obtained from Molecular probes (Eugene, Oregon, USA) in a dilution of 1:2000. While endothelial eNOS outlined blood vessels in the brain, brain-derived (neural) bNOS labelled three well-defined cell types in area 46 of the prefrontal cortex, viz. (a) bipolar cells, scattered through layers III to V, equipped with long dendrites which pass over the thickness of the cortex in a right angle to the pial surface, establishing dendritic bundles closely reminiscent of a columnar organization; (b) large multipolar cells, located mainly in layers V and VI, with axons which interconnect dendritic bundles of the bipolar cells and establish synapses with dendritic shafts and spines of the former; and (c) stellate cells, located in lamina II and III, which establish an axonal network in lamina zonalis (lamina I). This arrangement is most characteristic in area 46 of the prefrontal cortex; areas 10 and 12 display similar features. In contrast, the primary visual cortex (area 17), is lacking any sign of columnar organization. Localization of bNOS immunoreactivity is at marked variance to that of NADPH-diaphorase which labels large pyramidal cells in the primate cortex. Binding of alpha-bungarotoxin (BTX) which labels the alpha 7 subunit of nAChR is located in somata, dendrites and axons of interneurons scattered over the entire width of the prefrontal cortex; on the other hand, the monoclonal antibody mAb 35 which labels subunits alpha 1, alpha 3 and alpha 5 in the main immunogenic region of the receptor, visualizes apical dendritic shafts similar to those like bNOS. Strategic localization of bNOS in the primate prefrontal cortex fulfills criteria of producing a freely diffusing retrograde messenger molecule operative in signal transduction routes subserving topography and columnar organization of the cortex, as well as long-term potentiation and long-term depression phenomena underlying mnemonic and gnostic functions. Common occurrence of bNOS and nAChR in identical or similar structures in the prefrontal cortex suggests that interactions between nitrogen oxide and presynaptically released acetylcholine might be involved in the metasynaptic organization of the cerebral cortex, operating in a non-synaptic manner in maintaining optimal performance on cognitive tasks.
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PMID:Nitric oxide synthase and the acetylcholine receptor in the prefrontal cortex: metasynaptic organization of the brain. 1022 Jul 75

Extensive pharmacological evidence suggests that nitric oxide (NO) is a crucial transmitter for cerebellar long-term depression (LTD), a long-lasting decrease in efficacy of the synapses from parallel fibers onto Purkinje neurons, triggered by coincident presynaptic activity and postsynaptic depolarization. We now show that LTD cannot be induced in Purkinje neurons under whole-cell patch clamp in cerebellar slices from young adult mice genetically lacking neuronal nitric oxide synthase (nNOS). This genetic evidence confirms the essentiality of NO and nNOS for LTD in young adult rodents. Surprisingly, LTD in cells from nNOS knockout mice cannot be rescued by photolytic uncaging of NO and cGMP inside Purkinje neurons, although such stimuli circumvent acute pharmacological inhibition of nNOS and soluble guanylate cyclase in normal rodents. Also slices from knockout mice show no deficit in cGMP elevation in response to exogenous NO. Therefore, prolonged absence of nNOS allows atrophy of the signaling pathway downstream of cGMP.
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PMID:Absence of cerebellar long-term depression in mice lacking neuronal nitric oxide synthase. 1045 61

Cortical spreading depression (CSD) is associated with various short- and long-term physiological and neurochemical changes and has been shown to confer an increased susceptibility to accompanying ischemic injury or provide protection against a subsequent experimental ischemia. Nitric oxide is involved in the processes of ischemic injury and under certain conditions mediates cellular protection. To investigate the possibility that CSD-induced alterations in nitric oxide synthase (NOS) expression and activity occur and might be associated with the time-dependent enhancement or prevention by CSD of ischemic damage, this study examined the spatiotemporal changes in nNOS expression and activity in cerebral cortex following CSD. Anesthetized rats had unilateral CSD induced by a 10-min topical application of KCl and were killed at various times thereafter. CSD increased both nNOS mRNA and protein levels throughout layers II-III of cortex. nNOS mRNA in the affected neocortex was significantly increased by 30-90% at 2, 7, and 14 days (P < or = 0.05) compared with contralateral levels, but was not significantly above control values at 1-6 h, 1 day, and 28 days after CSD induction. Levels of [3H]-L-N(G)-nitroarginine binding to NOS were increased by 40-170% 7, 14, and 28 days (P < or = 0.01) after CSD in a similar, but delayed, profile to nNOS mRNA. Levels of nNOS-immunoreactivity were also increased in both neurons and astrocytes of ipsilateral cortex 7 and 14 days after CSD--confirmed by double-immunofluorescence localization. Ex vivo NOS activity in layers I-III of ipsilateral cortex was also increased by 30-50% (P < or = 0.01) at 7 and 14 days after CSD, times coincident with reported maximal ischemic protection. These results demonstrate that nNOS is up-regulated by cellular depolarization/depression occurring during CSD, or by resultant stimuli and suggest that "CSD-conditioned" cortex may be capable of producing appropriate levels of NO to mediate or contribute to protective/adaptive responses to subsequent physical ischemic injury.
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PMID:Prolonged induction of neuronal NOS expression and activity following cortical spreading depression (SD): implications for SD- and NO-mediated neuroprotection. 1061 50

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