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)

The membrane-permeant gas NO is a putative intercellular messenger that has been proposed on the basis of previous in vitro studies to be involved in synaptic plasticity, especially the induction of long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus and cortex. In the present study, the role of NO in synaptic plasticity has been investigated in vivo. In particular, the action of the novel and selective neuronal NO synthase (nNOS) inhibitor 7-nitro-indazole (7-NI) has been investigated on the induction of LTP and depotentiation (DP) of field EPSPs in CA1 of the hippocampus in vivo. Unlike previously studied nonselective NOS inhibitors, 7-NI does not increase arterial blood pressure. In vehicle-injected rats, high-frequency stimulation consisting of a series of trains at 200 Hz induced LTP. However, LTP induction was strongly inhibited in 7-NI (30 mg/kg, i.p.)-treated animals. The inhibitory effect of 7-NI on the induction of LTP was prevented by pretreatment with L-arginine, the substrate amino acid used by NOS. In control animals, low-frequency stimulation consisting of 900 stimuli at 10 Hz induced DP of previously established LTP, whereas in 7-HI-treated animals only a short-term depression was induced. This effect of 7-NI also was prevented by D-arginine. The LTP and DP induced in control animals in this study were NMDA receptor-dependent, the NMDA receptor antagonist 3-(R,S)-2-carboxypiperazin-4-yl-propyl-1- phosphonic acid inhibiting the induction of both forms of synaptic plasticity. The present experiments are the first to demonstrate that an NOS inhibitor blocks the induction of the synaptic component of LTP and DP in vivo and, therefore, these results strengthen evidence that the production of NO is necessary for the induction of LTP and DP.
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PMID:The selective neuronal NO synthase inhibitor 7-nitro-indazole blocks both long-term potentiation and depotentiation of field EPSPs in rat hippocampal CA1 in vivo. 861 7

Nitric oxide (NO) produced opposite effects on acetylcholine (ACh) release in identified neuroneuronal Aplysia synapses depending on the excitatory or the inhibitory nature of the synapse. Extracellular application of the NO donor, SIN-1, depressed the inhibitory postsynaptic currents (IPSCs) and enhanced the excitatory postsynaptic currents (EPSCs) evoked by presynaptic action potentials (1/60 Hz). Application of a membrane-permeant cGMP analog mimicked the effect of SIN-1 suggesting the participation of guanylate cyclase in the NO pathway. The guanylate cyclase inhibitor, methylene blue, blocked the NO-induced enhancement of EPSCs but only reduced the inhibition of IPSCs indicating that an additional mechanism participates to the depression of synaptic transmission by NO. Using nicotinamide, an inhibitor of ADP-ribosylation, we found that the NO-induced depression of ACh release on the inhibitory synapse also involves ADP-ribosylation mechanism(s). Furthermore, application of SIN-1 paired with cGMP-dependent protein kinase (cGMP-PK) inhibitors showed that cGMP-PK could play a role in the potentiating but not in the depressing effect of NO on ACh release. Increasing the frequency of stimulation of the presynaptic neuron from 1/60 Hz to 0.25 or 1 Hz potentiated the EPSCs and reduced the IPSCs. In these conditions, the potentiating effect of NO on the excitatory synapse was reduced, whereas its depressing effect on the inhibitory synapse was unaffected. Moreover the frequency-dependent enhancement of ACh release in the excitatory synapse was greatly reduced by the inhibition of NO synthase. Our results indicate that NO may be involved in different ways of modulation of synaptic transmission depending on the type of the synapse including synaptic plasticity.
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PMID:Opposite actions of nitric oxide on cholinergic synapses: which pathways? 871 Sep 38

We previously showed that the lymphocyte proliferation response was significantly suppressed in spontaneously hypertensive rats (SHR) and that this depressed response was due to excessive production of nitric oxide (NO) in macrophages and vascular smooth muscle cells (VSMC). Whether lymphocyte depression and activation of NO synthesis are related to age and development of hypertension remains unclear. The present study addresses such a correlation by examining the time course of development of hypertension, NO synthesis alteration and lymphocyte depression in SHR. Our results show that 1) SHR spleen cell proliferation responses are depressed at 4, 8, and 12 weeks and 1 year of age, with the lowest response occurring at 4 weeks of age; 2) this depressed response is corrected by either NO synthase inhibitor or removal of macrophages from spleen cells; 3) NO production by SHR spleen macrophages is significantly higher in all age groups; 4) upon stimulation with lipopolysaccharide or cytokines, SHR VSMC produce a significantly greater amount of NO in all age groups; 5) the increase in NO synthesis in VSMC correlates significantly with the rise in blood pressure in SHR. However, statistical correlation analysis suggests that lymphocyte depression and the alteration of NO synthesis in macrophages were not associated with either age or increased blood pressure in SHR. On the contrary, the activation of NO synthesis in VSMC can be statistically correlated with elevated blood pressure throughout the development of hypertension in SHR. Nevertheless, the results also suggest that a general alteration in the NO synthesis system may exist in SHR.
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PMID:Activation of nitric oxide synthesis in vascular smooth muscle cells and macrophages during development in spontaneously hypertensive rats. 872 40

Microglia and astrocytes are transformed into reactive glia (RG) by brain disease and normal function. Eicosanoids and nitric oxide (NO), two intercellular mediators, may influence gliosis. We investigated how drugs that alter production of these paracrine signals effect induction of glial reactivity from spreading depression. Unilateral (left) neocortical spreading depression was induced in 95 halothane anesthetized rats by intracortical injections of 0.5 M KCl, with or without drug treatment (five animals/group). Immunohistochemical staining (IS) intensity using the OX-42 and anti-glial fibrillary acidic protein (GFAP) antibodies determined reactivity in microglia and astrocytes, respectively. After 3 days, brains were processed for OX-42 and GFAP-IS and mean optical densities (OD) of IS were measured. Average OD's (for OX-42) and the log ratio (left/right) of OD's (OX-42 and GFAP) were compared to normal animals. Spreading depression induced significant log ratios for both OX-42- and GFAP-IS (P's < 0.01). However, dexamethasone (a glucocorticoid), nordihydroguaiaretic acid (a lipoxygenase inhibitor), and nitroprusside (a NO donor) prevented significant left sided and log ratio OD values for microglia (P's > 0.05). L-Name, a NO synthase inhibitor, caused significant increases in left and right OD's for microglia (P's < 0.05). Mepacrine, a phospholipase A2 inhibitor, Indomethacin, a cyclooxygenase inhibitor, and phenylephrine, an adrenergic agonist, did not prevent induction of significant OX-42 log ratios (P's < 0.01, 0.05, 0.01), and resulted in increases in left side OD's (P's < 0.01, 0.05, 0.05). Significant GFAP log ratios occurred after spreading depression in all drug groups, P's < 0.01. Thus, induction of reactivity in microglia is more sensitive to eicosanoids and NO than in astrocytes.
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PMID:Eicosanoids and nitric oxide influence induction of reactive gliosis from spreading depression in microglia but not astrocytes. 872 5

1. We performed experiments to examine the effects of an anti-fungal imidazole compound, econazole, on the regulation and effects of lipopolysaccharide-inducible nitric oxide synthase (iNOS) activity in rat aortic rings and cultured J774 murine macrophage cells. 2. In endothelium-intact rings of thoracic aorta, phenylephrine caused a concentration-dependent contraction with EC50 of 1.9 +/- 0.15 x 10(-8) M (n = 5). Following incubation with lipopolysaccharide (LPS, 5 micrograms ml-1) for 8 h there was a right-shift in the concentration-response curve (EC50 3.1 +/- 0.28 x 10(-7) M, P < 0.05) with a depression in the maximum contraction from 1.44 +/- 0.25 g to 0.86 +/- 0.26 g (n = 4). Co-incubation of rings with econazole (1 x 10(-5) M) partially inhibited the LPS-induced loss of reactivity to phenylephrine (EC50 6.5 +/- 0.72 x 10(-8) M) and fully inhibited the reduction in maximum tension (1.49 +/- 0.19 g; n = 5). 3. In J774 cells, incubation with LPS (10 micrograms ml-1, 24 h) resulted in significant nitrite production that was inhibited by co-incubation with econazole (IC50 5.0 +/- 0.9 x 10(-6) M; n = 5). In cells stimulated with LPS, production of L-[3H]-citrulline from L-[3H]-arginine was 6.41 +/- 0.22 pmol mg-1 protein min-1 (n = 3). This was inhibited by 92 +/- 6% by addition of NG-monomethyl-L-arginine (L-NMMA, 1 x 10(-3) M; n = 3) to the homogenate but not by econazole (1 x 10(-5) M; n = 3). In contrast pretreatment of cells with econazole (1 x 10(-5) M) markedly reduced the LPS-induced [3H]-citrulline production (0.86 +/- 0.053 pmol mg-1 protein min-1; P < 0.01; n = 3). 4. In cells treated with LPS and econazole, L-[3H]-citrulline production was restored in a concentration-dependent manner by addition of calmodulin (1 x 10(-8)-3 x 10(-7) M) with an IC50 of 4.2 +/- 0.9 x 10(-8) M. 5. We have shown that econazole inhibits the functional and biochemical activity of iNOS in rat aortic rings and cultured J774 cells. Treatment of cells with econazole renders the NO synthase functionally inactive. In econazole-treated cells enzyme activity is restored by calmodulin suggesting that econazole may inhibit the binding of this essential co-factor to the enzyme following its production. These studies may have implications for the design of novel anti-inflammatory agents working through the L-arginine-nitric oxide pathway.
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PMID:Functional effects of econazole on inducible nitric oxide synthase: production of a calmodulin-dependent enzyme. 888 96

Ethanol (ETOH) inhibits the immune response to endotoxemia. The early stage of endotoxin (LPS)-induced shock is associated with an acute phase cardiovascular depression (APCD). Release of platelet activating factor (PAF) and tumor necrosis factor alpha (TNF alpha) with upregulation of nitric oxide (NO) production may initiate the APCD. Since ETOH inhibits induction of NO synthase (iNOS) mNRA by LPS, we postulate that ETOH may mask the APCD associated with endotoxemia. To test this, Sprague-Dawley rats (280-320 g, n = 5-6/group) were given LPS [0.75 mg/kg, intravenously (i.v.)] or PAF (10 to 150 micrograms/kg, i.v.) 30 min after administration of sterile saline (PBS), BN-5073 a mixed PAF antagonist (0.50 microgram/kg, i.v.), or ETOH [2.2-5.5 g/kg, intraperitoneally (i.p.)]. Cardiovascular parameters and plasma concentrations of nitrate and nitrite (RNI), ETOH, TNF alpha, and neutrophil (PMN) generation of RNI were measured. LPS and PAF both produced APCD. LPS-induced APCD was associated with tachycardia, elevated plasma TNF alpha and RNI, and ex vivo generation of RNI by PMNs. ETOH and BN-50730 prevented LPS-induced APCD and increases in RNI and TNF alpha. ETOH, however, increased the mortality associated with APCD. PAF produced only hypotension, bradycardia and elevated plasma levels of TNF alpha. ETOH and LNMMA did not affect PAF-induced APCD. BN-50730 inhibited PAF-induced APCD and plasma TNF alpha. We conclude that 1) ETOH inhibits the APCD and induction of NO characteristic of endotoxemia and 2) ETOH-induced suppression of LPS-mediated APCD may be mediated in part by suppression of release of intracellular PAF. Ethanol may increase the morbidity and mortality of endotoxemia by masking the hypotension and humoral changes characteristic of early endotoxemia thereby delaying appropriate therapy and by diminution of the protective effects of endogenous NO.
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PMID:Ethanol suppresses endotoxin but not platelet activating factor-induced hypotension and nitric oxide. 890 80

Progressive cholinergic axonal dystrophy, cholinergic denervation, and generalized gliosis begin in the prosimian primate species Otolemur at 10% of maximum life span. In these same animals, extensive cerebral beta-amyloidosis follows relatively more abruptly at 50% of maximum life span. In contrast, even at maximum life span, the prosimian primate species Galago senegalensis Moholi, Microcebus murinus, and Eulemur fulvus collaris and insectivore species T. belangeri are either spared or much less affected. In this report, we further document this progressive cholinergic denervation in Otolemur which involves first projections of the pedunculopontine nucleus (PPN, CH5-6) and later projections of CH1-4 cholinergic nuclei, as well as other noncholinergic pathways. Affected cholinergic cell bodies and axons contain abnormal mitochondria with increased content of manganese superoxide dismutase (MnSOD). This syndrome correlates with moderate copper deficiency marked by diminished liver copper levels and cuproenzyme activities, carnitine deficiency possibly secondary to renal Fanconi syndrome, and evidence for stress inflammatory response activation. Mitochondrial pathology was observed in pancreatic islet cells, proximal renal tubule epithelial cells, and choroid plexus epithelial cells, and it involved central cholinergic neurons. In Otolemur garnetti, the degree of central cholinergic injury directly correlated to depression of liver copper stores. The Otolemur syndrome involves "sentinel" central cholinergic injury and selective mitochondrial pathology in cell classes defined by high mitochondrial content and/or metabolic activity and high content of nitric oxide synthetase and MnSOD. Environmental factors affecting copper and carnitine metabolism could interact with genetic defects or traits to produce abnormal and aggressive aging of Otolemur. Subclinical, cell-class specific mitochondrial dysfunction in these prosimian primates may be a model for human neurodegenerative diseases.
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PMID:Cholinergic axonal dystrophy and mitochondrial pathology in prosimian primates. 891 3

Diverse roles in cellular functions have been ascribed to nitric oxide (NO), and its involvement in induction of long-term depression in cerebellar Purkinje cells has been demonstrated. Manipulations of NO concentration or its synthesis in cerebellar tissues therefore provide a means for investigating roles of NO in cerebellar functions at both cellular and behavioral levels. We tested adaptive control of locomotion to perturbation in cats, and found that this form of motor learning was abolished by application of either an inhibitor of NO synthase or a scavenger of NO to the cerebellar cortical locomotion area. This finding supports the view that NO in the cerebellum plays a key role in motor learning.
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PMID:Nitric oxide plays a key role in adaptive control of locomotion in cat. 891 84

Long-term depression (LTD) of synaptic transmission between parallel fibres and Purkinje cells is a well-known example of synaptic plasticity taking place in the cerebellum. Nitric oxide (NO) has been implicated in synaptic plasticity in other brain areas, but its function in cerebellar LTD is controversial. Even when an involvement is suggested, the NO signal transduction pathway is unclear. One candidate is the cyclic GMP-synthesizing enzyme, soluble guanylyl cyclase, whose activity in the brain and elsewhere is powerfully stimulated by NO. By recording intracellularly from Purkinje cells in cerebellar slices, we demonstrate that blockade of NO synthase completely inhibits LTD induced by pairing parallel fibre stimulation with postsynaptic Ca2+ spike firing. LTD was also blocked by intracellular application of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a recently identified potent and selective inhibitor of soluble guanylyl cyclase. These findings indicate that soluble guanylyl cyclase is required for cerebellar LTD and suggest that this enzyme, located within Purkinje cells, transduces the NO signal in this form of synaptic plasticity.
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PMID:Long-term depression in rat cerebellum requires both NO synthase and NO-sensitive guanylyl cyclase. 892 13

Pontine cholinergic neurotransmission is known to play a key role in the regulation of rapid eye movement (REM) sleep and to contribute to state-dependent respiratory depression. Nitric oxide (NO) has been shown to alter the release of acetylcholine (ACh) in a number of brain regions, and previous studies indicate that NO may participate in the modulation of sleep/wake states. The present investigation tested the hypothesis that inhibition of NO synthase (NOS) within the medial pontine reticular formation (mPRF) of the unanesthetized cat would decrease ACh release, inhibit REM sleep, and prevent cholinergically mediated respiratory depression. Local NOS inhibition by microdialysis delivery of N(G)-nitro-L-arginine (NLA) significantly reduced ACh release in the cholinergic cell body region of the pedunculopontine tegmental nucleus and in the cholinoceptive mPRF. A second series of experiments demonstrated that mPRF microinjection of NLA significantly reduced the amount of REM sleep and the REM sleep-like state caused by mPRF injection of the acetylcholinesterase inhibitor neostigmine. Duration but not frequency of REM sleep epochs was significantly decreased by mPRF NLA administration. Injection of NLA into the mPRF before neostigmine injection also blocked the ability of neostigmine to decrease respiratory rate during the REM sleep-like state. Taken together, these findings suggest that mPRF NO contributes to the modulation of ACh release, REM sleep, and breathing.
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PMID:Pontine nitric oxide modulates acetylcholine release, rapid eye movement sleep generation, and respiratory rate. 898 99

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