Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of different neuroactive substances on morphine-induced respiratory depression were studied in medullary respiration-related structures using in vitro brainstem-spinal cord preparation from 1 to 4-day-old rats. Application of morphine (10 microM) reduced respiratory rhythm (fR) as measured by C4 ventral root activity. The depressant effects of morphine were reversed by acetylcholine (10 microM), substance P (50 nM), thyrotropin releasing hormone (TRH) (100 nM) and forskolin (10 microM). The adenosine receptor antagonist, theophylline (100 microM), the dopamine receptors antagonist, haloperidol (10 microM), the cyclooxygenase inhibitor, indomethacin (10 microM) and the phospholipase A(2) inhibitor, quinacrine (10 microM) had no effect on morphine-induced respiratory depression.
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PMID:Effects of neuroactive substances on the morphine-induced respiratory depression; an in vitro study. 1108 3

Long-term potentiation (LTP) and long-term depression (LTD) are two electrophysiological models that have been studied extensively in recent years as they may represent basic mechanisms in many neuronal networks to store certain types of information. In several brain regions, it has been shown that these two forms of synaptic plasticity require sufficient dendritic depolarization, with the amplitude of the calcium signal being crucial for the generation of either LTP or LTD. The rise in calcium concentration mediated by the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been proposed to stimulate various calcium-dependent enzymatic processes that could convert the induction signal into long-lasting changes in synaptic structure; protein kinases and phosphatases have so far been considered predominantly with regard to LTP and LTD formation. According to several lines of experimental evidence, changes in synaptic function observed with LTP and LTD are thought to be the result of modifications of postsynaptic currents mediated by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. Moreover, it has become apparent recently that activation of the calcium-dependent enzyme phospholipase A2 (PLA2) could be part of the molecular mechanisms involved in alterations of AMPA receptor properties during long-term changes in synaptic operation. In the present review, we will first describe the results that indicate a critical role of the phospholipases in regulating synaptic function. Next, sections will be devoted to the effects of PLA2 and phospholipids on the binding properties of glutamate receptors, and a revised biochemical model will be presented as an attempt to integrate the PLA2 enzyme into the mechanisms ( in particular kinases and phosphatases) that participate in adaptive neural plasticity. Finally, we will review data relevant to the issue of selective changes in AMPA binding after environmental enrichment and LTP.
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PMID:Modification of glutamate receptors by phospholipase A2: its role in adaptive neural plasticity. 1109 49

In cerebellar slices conjunctive pairing of parallel fibre (PF) stimulation with depolarization of Purkinje cells (PCs) induces a long-term depression (LTD) of PF synaptic transmission that spreads to unpaired PF inputs to the same cell. Inhibitors of NO synthase (7-nitro-indazole), soluble guanylate cyclase (ODQ) and PKG (KT5823) all prevented depression at each of two independent PF pathways to a single PC. Inhibition of NOS also unmasked a platelet activating factor (PAF)-mediated synaptic potentiation of possible presynaptic origin. LTD was also prevented by the phospholipase A2 inhibitor OBAA but was rescued by co-perfusion with arachidonic acid. We conclude that NO and diffusible products of phospholipase A2 metabolism are potential mediators of the spread of cerebellar plasticity at the single cell level.
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PMID:Roles for nitric oxide and arachidonic acid in the induction of heterosynaptic cerebellar LTD. 1120 Oct 73

Use of the anticancer antibiotic doxorubicin continues to be limited by its cumulative dose-related cardiotoxicity. Our study reports inhibition of myocardial intracellular calcium-independent phospholipase A(2) (iPLA(2)) activity by clinically relevant concentrations of the drug. The effect was first shown in vitro using suspensions of freshly isolated rat and rabbit cardiomyocytes. Addition of 0.1-10 microM doxorubicin to these cells led to a concentration- and time-dependent inhibition of total iPLA(2), as measured using (16:0, [(3)H]18:1) plasmenylcholine and phosphatidylcholine substrates in the presence or absence of calcium. Subcellular fractionation into cytosolic and membrane fraction revealed that the drug selectively inhibits membrane-associated iPLA(2) activity, without altering activity of the cytosolic enzyme. Doxorubicin treatment of cells prelabeled with [H(3)]arachidonic acid led to a depression of baseline arachidonic acid release levels, corroborating iPLA(2) inhibition. Reducing agents blocked PLA(2) inhibition in cardiomyocyte suspensions, suggesting that the doxorubicin effect is mediated by oxidation of susceptible cysteines. In vivo experiments, in which adults rats were i.v. injected with a bolus dose of 4 mg/kg doxorubicin, confirmed in vitro findings, revealing a 2-fold decrease in membrane-associated Ca(2+)-independent iPLA(2) activity in the heart tissue of treated animals. The observed phenomenon has important implications for myocyte signaling cascades and membrane remodeling.
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PMID:Clinical concentrations of doxorubicin inhibit activity of myocardial membrane-associated, calcium-independent phospholipase A(2). 1135 21

Plasmalogens are glycerophospholipids of neural membranes containing vinyl ether bonds. Their synthetic pathway is located in peroxisomes and endoplasmic reticulum. The rate-limiting enzymes are in the peroxisomes and are induced by docosahexaenoic acid (DHA). Plasmalogens often contain arachidonic acid (AA) or DHA at the sn-2 position of the glycerol moiety. The receptor-mediated hydrolysis of plasmalogens by cytosolic plasmalogen-selective phospholipase A2 generates AA or DHA and lysoplasmalogens. AA is metabolized to eicosanoids. The mechanism of signaling with DHA is not known. The plasmalogen-selective phospholipase A2 differs from other intracellular phospholipases A2 in molecular mass, kinetic properties, substrate specificity, and response to glycosaminoglycans, gangliosides, and sialoglycoproteins. A major portion of [3H]DHA incorporated into neural membranes is found at the sn-2 position of ethanolamine glycerophospholipids. Studies with a mutant cell line defective in plasmalogen biosynthesis indicate that the incorporation of DHA is reduced in this RAW 264.7 cell line by 50%. In contrast, the incorporation of AA remains unaffected. This is reversed completely when the growth medium is supplemented with sn-1-hexadecylglycerol, suggesting that DHA can be selectively targeted for incorporation into plasmalogens. We suggest that deficiencies of DHA and plasmalogens in peroxisomal disorders, Alzheimer's disease (AD), depression, and attention deficit hyperactivity disorders (ADHD) may be responsible for abnormal signal transduction associated with learning disability, cognitive deficit, and visual dysfunction. These abnormalities in the signal-transduction process can be partially corrected by supplementation with a diet enriched with DHA.
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PMID:Plasmalogens, phospholipase A2, and docosahexaenoic acid turnover in brain tissue. 1147 81

The effects of Pa-1G, a phospholipase A(2) (PLA(2)) from the venom of the Australian king brown snake (Pseudechis australis) were determined on the release of acetylcholine, muscle resting membrane potential and motor nerve terminal action potential at mouse neuromuscular junction. Intracellular recording from endplate regions of mouse triangularis sterni nerve-muscle preparations revealed that Pa-1G (800 nM) significantly reduced the amplitude of endplate potentials within 10 min exposure. The quantal content of endplate potentials was decreased to 58+/-6% of control after 30 min exposure to 800 nM Pa-1G. The toxin also caused a partial depolarisation of mouse muscle fibres within 60 min exposure. Extracellular recording of action potentials at motor nerve terminals showed that Pa-1G reduced the waveforms associated with both sodium and potassium conductances. To investigate whether this was a direct or indirect effect of the toxin on these ionic currents, whole cell patch clamp experiments were performed using human neuroblastoma (SK-N-SH) cells and B82 mouse fibroblasts stably transfected with rKv1.2. Patch clamp recording experiments confirmed that potassium currents sensitive to alpha-dendrotoxin recorded from B82 cells and sodium currents in SK-N-SH cells were not affected by the toxin. Since neither facilitation of acetylcholine release at mouse neuromuscular junction nor depression of potassium currents in B82 cells has been observed, the apparent blockade of potassium currents at mouse motor nerve endings induced by the toxin is unlikely to be due to a selective block of potassium channels.
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PMID:An electrophysiological study on the effects of Pa-1G (a phospholipase A(2)) from the venom of king brown snake, Pseudechis australis, on neuromuscular function. 1160 81

Plants and animals that can survive dehydration accumulate high concentrations of disaccharides in their cells and tissues during desiccation. These sugars are necessary both for the depression of the membrane phase transition temperature of the dry lipid and for the formation of a carbohydrate glass. In the past decade, however, it has become clear that certain types of adventitious enzymatic reactions are possible at low water contents, which along with free-radical mediated damage, can cause hydrolysis of lipids and loss of membrane barrier function. Disaccharides do not necessarily prevent these types of reactions, which suggests that other compounds might also be necessary for protecting organisms from this type of degradation during anhydrobiosis. Arbutin, one possible example, accumulates in large quantities in certain resurrection plants and has been shown to inhibit phospholipase A(2) activity at low water contents. The direct effect of arbutin on membranes under stress conditions depends on the membrane lipid composition. It can serve a protective function during desiccation- or freeze/thaw-induced stress in the presence of nonbilayer-forming lipids or a disruptive function in their absence. Other possible amphiphiles, including certain naturally occurring flavonols, may serve as anti-oxidants and some might have similar lipid composition-dependent effects. Such compounds, therefore, are likely to be localized near specific membranes, where they might provide the greatest benefit at the least liability to the organism.
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PMID:Looking beyond sugars: the role of amphiphilic solutes in preventing adventitious reactions in anhydrobiotes at low water contents. 1186 77

Phospholipids make up 60 per cent of the dry weight of the brain. They are essential for neuronal and especially for synaptic structure and play key roles in the signal transduction responses to dopamine, serotonin, glutamate and acetyl choline. The unsaturated fatty acid components of phospholipids are abnormal in depression, with deficits of eicosapentaenoic acid and other omega-3 fatty acids and excesses of the omega-6 fatty acid arachidonic acid. Correction of this abnormality by treatment with eicosapentaenoic acid improves depression. The fatty acid abnormalities provide a rational explanation for the associations of depression with cardiovascular disease, immunological activation, cancer, diabetic complications and osteoporosis. The abnormalities cannot be explained by diet, although diet may attenuate or exacerbate their consequences. A number of enzyme abnormalities could explain the phenomena: phospholipase A(2), and coenzyme A-independent transacylase are strong candidates. Copyright 2001 John Wiley & Sons, Ltd.
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PMID:Phospholipid metabolism and depression: the possible roles of phospholipase A2 and coenzyme A-independent transacylase. 1240 97

N-type Ca(2+) channels participate in acute activity-dependent processes such as regulation of Ca(2+)-activated K(+) channels and in more prolonged events such as gene transcription and long-term depression. A slow postsynaptic M(1) muscarinic receptor-mediated modulation of N-type current in superior cervical ganglion neurons may be important in regulating these processes. This slow pathway inhibits N-type current by using a diffusible second messenger that has remained unidentified for more than a decade. Using whole-cell patch-clamp techniques, which isolate the slow pathway, we found that the muscarinic agonist oxotremorine methiodide not only inhibits currents at positive potentials but enhances N-type current at negative potentials. Enhancement was also observed in cell-attached patches. These findings provide evidence for N-type Ca(2+)-current enhancement by a classical neurotransmitter. Moreover, enhancement and inhibition of current by oxotremorine methiodide mimics modulation observed with direct application of a low concentration of arachidonic acid (AA). Although no transmitter has been reported to use AA as a second messenger to modulate any Ca(2+) current in either neuronal or nonneuronal cells, we nevertheless tested whether a fatty acid signaling cascade was involved. Blocking phospholipase C, phospholipase A(2), or AA but not AA metabolism minimized muscarinic modulation of N-type current, supporting the participation of these molecules in the slow pathway. A role for the G protein G(q) was also confirmed by blocking muscarinic modulation of Ca(2+) currents with anti-G(qalpha) antibody. Our finding that AA participates in the slow pathway strongly suggests that it may be the previously unknown diffusible second messenger.
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PMID:Arachidonic acid mediates muscarinic inhibition and enhancement of N-type Ca2+ current in sympathetic neurons. 1249 47

Fluoxetine, a selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor, is used widely to treat depression and related disorders. By inhibiting presynaptic 5-HT reuptake, fluoxetine is thought to act by increasing 5-HT in the synaptic cleft, thus 5-HT binding to postsynaptic 5-HT(2A/2C) receptors. These receptors can be coupled via a G-protein to phospholipase A(2) (PLA(2)), which when activated releases the second messenger arachidonic acid from synaptic membrane phospholipids. To image this activation, fluoxetine (10 mg/kg) or saline vehicle was administered i.p. to unanesthetized rats, and regional brain incorporation coefficients k(*) of intravenously injected radiolabeled arachidonic acid were measured after 30 min. Compared with vehicle, fluoxetine significantly increased k(*) in prefrontal, motor, somatosensory, and olfactory cortex, as well as in the basal ganglia, hippocampus, and thalamus. Many of these regions demonstrate high densities of the serotonin reuptake transporter and of 5-HT(2A/2C) receptors. Brain stem, spinal cord, and cerebellum, which showed no significant response to fluoxetine, have low densities of the transporters and receptors. The results show that it is possible to image quantitatively PLA(2)-mediated signal transduction in vivo in response to fluoxetine.
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PMID:Imaging brain phospholipase A2-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats. 1278 22


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