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)

Cerebellar long-term depression (LTD) may be reliably induced in the cultured Purkinje neuron when glutamate pulses and Purkinje neuron depolarization are applied together 6 times. When the number of these conjunctive stimuli was reduced to 2, a short-term depression (STD) lasting 20-40 min was induced in 4/12 cells. The enzyme phospholipase A2 cleaves membrane phospholipids causing liberation of free unsaturated fatty acids, which in turn synergistically activate protein kinase C when present with diacylglycerol and Ca. Application of free unsaturated fatty acids with 2 conjunctive stimuli resulted in an apparent conversion of STD cases to LTD. Application of phospholipase A2 inhibitors during 6 conjunctions converted LTD to STD. These findings suggest a model in which liberation of unsaturated fatty acids by phospholipase A2 contributes to a synergistic activation of protein kinase C, the full activation of which results in LTD induction, and the partial activation of which results in STD induction.
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PMID:Phospholipase A2 controls the induction of short-term versus long-term depression in the cerebellar Purkinje neuron in culture. 884 62

Low-frequency stimulation is associated with long-term depression (LTD) of synaptic efficacy in various brain structures. Like long-term potentiation (LTP), homosynaptic LTD in area CA1 of the hippocampus appears to require NMDA receptor activation, changes in postsynaptic calcium concentration and phospholipase A2 (PLA2) activation. Arachidonic acid (AA) is released after the activation of calcium-dependent phospholipases and free AA is rapidly metabolized to a family of bioactive products (the eicosanoids) which are thought to be both intracellular and extracellular messengers. In the present study, we investigated the involvement of the cyclooxygenase and lipoxygenase pathways of AA metabolism in the formation of homosynaptic LTD in the rat hippocampus. Stimulation at 1 Hz for 15 min was used to produce homosynaptic depression in area CA1 of hippocampal slices. LTD induction was partially blocked by bromophenacyl bromide (50-100 microM), a selective PLA2 inhibitor, and by the a nonselective lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 100 microM). In contrast, the specific cyclooxygenase blocker indomethacin (100 microM) did not significantly reduce hippocampal LTD. Since NDGA interferes with LTD formation, we examined whether specific inhibitors of 5- and 12-lipoxygenases were capable of blocking LTD expression. The 12-lipoxygenase inhibitor baicalein at a concentration of 50 microM reduced LTP formation when given in the bath, an effect that was less pronounced with the 5-lipoxygenase inhibitor AA-861. These data suggest that the activation of endogenous PLA2 and the formation of 12-lipoxygenase metabolites of AA may be important factors controlling the expression of hippocampal LTD.
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PMID:Involvement of the 12-lipoxygenase pathway of arachidonic acid metabolism in homosynaptic long-term depression of the rat hippocampus. 888 86

Repetitive spreading depression (SD) waves, involving depolarization of neurons and astrocytes and up-regulation of glucose consumption, is thought to lower the threshold of neuronal death during and immediately after ischemia. Using rat models for SD and focal ischemia we investigated the expression of cyclooxygenase-1 (COX-1), the constitutive form, and cyclooxygenase-2 (COX-2), the inducible form of a key enzyme in prostaglandin biosynthesis and the target enzymes for nonsteroidal anti-inflammatory drugs. Whereas COX-1 mRNA levels were undetectable and uninducible, COX-2 mRNA and protein levels were rapidly increased in the cortex, especially in layers 2 and 3 after SD and transient focal ischemia. The cortical induction was reduced by MK-801, an N-methyl-D-aspartic acid-receptor antagonist, and by dexamethasone and quinacrine, phospholipase A2 (PLA2) inhibiting compounds. MK-801 acted by blocking SD whereas treatment with PLA2 inhibitors preserved the wave propagation. NBQX, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate-receptor antagonist, did not affect the SD-induced COX-2 expression, whereas COX-inhibitors indomethacin and diclofenac, as well as a NO synthase-inhibitor, NG-nitro-L-arginine methyl ester, tended to enhance the COX-2 mRNA expression. In addition, ischemia induced COX-2 expression in the hippocampal and perifocal striatal neurons and in endothelial cells. Thus, COX-2 is transiently induced after SD and focal ischemia by activation of N-methyl-D-aspartic acid-receptors and PLA2, most prominently in cortical neurons that are at a high risk to die after focal brain ischemia.
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PMID:Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. 917 47

The mechanisms by which diabetes impairs cognitive function are not well-established. In the present study, we determined the electrophysiological and biochemical nature of disturbances in the mechanism of long-term potentiation (LTP) in diabetic rats. As previously reported, the administration of streptozotocin (STZ) was found to reduce the magnitude of LTP in the CA1 region of the hippocampus, while the same treatment did not interact with the capacity of the hippocampus to generate long-term depression induced by low-frequency stimulation. In addition, STZ treatment did not modify the component of excitatory postsynaptic potentials mediated by activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, suggesting that NMDA receptor function remained intact in STZ-treated slices. At the biochemical level, the capacity of calcium to increase [3H](RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid (3H-AMPA) binding to glutamate/AMPA receptors in rat brain tissue sections was markedly affected in most regions of the hippocampus of STZ-treated rats. Moreover, changes in 3H-AMPA binding properties elicited by both exogenous phospholipase A2 and melittin, a potent activator of endogenous phospholipases, were also altered in synaptoneurosomes from diabetic rats. Taken together, the present data suggest that the loss of LTP maintenance in STZ-treated rats is more likely the result of disruption of calcium-dependent processes that are suspected to modulate postsynaptic AMPA receptors during synaptic potentiation. Understanding the biochemical factors participating in the impairment of AMPA receptor modulation might provide important clues revealing the very basis of memory deficits in diabetes.
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PMID:Impaired modulation of AMPA receptors by calcium-dependent processes in streptozotocin-induced diabetic rats. 936 22

In the CA1 region of rat hippocampal slices, H2O2 (0.294-2.94 mM) caused initial augmentation, and subsequent long-lasting depression, of population spikes and excitatory postsynaptic potentials. The effect of H2O2 may not be mediated by its degradation product, hydroxyl radicals, because an iron chelator deferoxamine did not block the effect. A catalase inhibitor 3-amino-1,2,4-triazole only modestly attenuated the initial augmentation, suggesting that the effect of H2O2 is not attributable to catalase-dependent O2 generation, either. An N-methyl-D-aspartate receptor antagonist DL-2-amino-5-phosphonovaleric acid had no influence on the effect of H2O2, whereas a gamma-aminobutyric acid type A receptor channel blocker picrotoxin attenuated long-lasting depression, indicating that gamma-aminobutyric acid-mediated inhibition is altered during the depression phase. The initial augmentation but not subsequent depression was attenuated by a phospholipase A2/C inhibitor 4-bromophenacyl bromide, suggesting the involvement of lipid signaling molecule(s) in the enhancement of excitatory synaptic transmission. These results suggest that H2O2 regulates hippocampal synaptic transmission via multiple mechanisms.
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PMID:Biphasic effect of hydrogen peroxide on field potentials in rat hippocampal slices. 943 Apr 16

Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses in the cerebellum has been the first established example of enduring decrease of synaptic efficacy in the central nervous system. This review focuses on the underlying cellular and molecular mechanisms. Thus, at the level of the postsynaptic membranes of PCs, induction of LTD requires concommitent activation of voltage-gated calcium channels (VGCCs) and of ionotropic and metabotopic glutamate receptors, of the alpha-amino-3 hydroxy-5-methyl-isoxalone-4-propionate (AMPA) and mGluR1 alpha types respectively. Subsequent intracellular cascades involve production of nitric oxide from arginine and of cGMP, activation of phospholipase A2 and of several protein kinases including protein kinase C and tyrosine kinases. Activation of protein kinase G and of phosphatases are also likely to be involved in LTD induction. In contrast, there are still uncertainties concerning a major role of release of calcium from internal stores in LTD induction. Finally protein synthesis is required for a late phase of LTD to occur. All available experimental evidence points towards a postsynaptic site for LTD expression. In particular, electrophysiological data demonstrate a genuine modification of the functional properties of AMPA receptors of PCs during LTD, and immunocytochemical evidence suggests that this might result from a phosphorylation of these receptors.
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PMID:Long-term depression of synaptic transmission in the cerebellum: cellular and molecular mechanisms revisited. 960 1

At the site of a wound or an infection, localized production of colony-stimulating factor-1 (CSF-1) by resident macrophages is chemotactic for circulating monocytes. Several intracellular signaling pathways, including those initiated in response to activation of phospholipase A2 (PLA2) have been proposed to play a role in the regulation of CSF-1 gene expression. The goal of these studies was to determine whether PLA2 is required for the initial increase in CSF-1 gene expression in serum- or IL-1 alpha-stimulated growth-arrested fibroblasts. IL-1 alpha- or serum-stimulation of growth-arrested fibroblasts had no effect on PLA2 enzyme activity and inhibitors of cytosolic or Ca(2+)-independent PLA2 activity had no effect on IL-1 alpha- or serum-mediated increases in CSF-1 mRNA levels. High concentrations of the PLA2 inhibitors, 4-bromophenacyl lactone and quinacrine, resulted in a generalized decrease in cellular mRNA levels. Our results, obtained in fibroblasts, suggest treatment with 4-bromophenacyl lactone or quinacrine, instead of inhibiting PLA2 activity specifically, results in a generalized depression of cellular mRNA levels. These data demonstrate that the initial increase in CSF-1 gene expression in growth-arrested fibroblasts treated with serum or IL-1 alpha occurs through a PLA2-independent mechanism.
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PMID:PLA2-independent induction of CSF-1 gene expression in growth-arrested fibroblasts. 965 Apr 46

The synaptic modifications underlying long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission in various brain structures may result from changes in the properties of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. In the present study, we report that treatment of rat synaptoneurosomes with increasing concentrations of phospholipase A2 (PLA2) produces a biphasic effect on AMPA receptor binding, with low concentrations causing a decrease and high concentrations an increase in agonist binding. Analysis of the saturation kinetics of 3H-AMPA binding revealed that the biphasic effect of PLA2 was due to modifications in receptor affinity and not to changes in the maximum number of binding sites for AMPA receptors. The 12-lipoxygenase inhibitors preferentially reduced PLA2-induced decrease in AMPA binding and treatment of hippocampal synaptoneurosomes with arachidonic acid (AA) or 12-HPETE, the first metabolite generated from the hydrolysis of AA by 12-lipoxygenases, decreased 3H-AMPA binding. Moreover, electrophysiological experiments indicated that the 12-lipoxygenase inhibitor baicalein totally blocked LTD formation in area CA1 of hippocampal slices. The decrease in 3H-AMPA binding elicited by low concentrations of PLA2, as well as the level of LTD, were partially reduced by AA-861, a 5-lipoxygenase inhibitor, while the cyclooxygenase inhibitor indomethacin did not prevent LTD formation or the effects of PLA2 on 3H-AMPA binding. Our results provide evidence for a possible involvement of lipoxygenase metabolites in the regulation of AMPA receptor during synaptic depression. In addition, they strongly support the idea that the same biochemical pathway, i.e., NMDA receptor activation and endogenous PLA2 stimulation, may represent a common mechanism resulting in AMPA receptor alterations for both LTP and LTD formation.
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PMID:Bidirectional modulation of AMPA receptor properties by exogenous phospholipase A2 in the hippocampus. 966 43

Pregnancy can exert suppressive effects on chronic inflammatory conditions. We have previously demonstrated a depression in polymorphonuclear leukocyte (PMN) respiratory burst during pregnancy which could explain this amelioration. To elucidate the biochemical mechanism, we have examined PMN phospholipase A2 (PLA2) activity and its relationship to cellular and circulating fatty acids in pregnant women (30 to 34 weeks) and nonpregnant controls. PMN PLA2 activity was determined by arachidonic acid (AA) and leukotriene B4 (LTB4) release, respiratory burst activity was determined by lucigenin-enhanced chemiluminescence, and total serum and PMN fatty acid levels were determined by gas-liquid chromatography. AA release was significantly reduced for pregnancy PMNs in response to N-formyl-met-leu-phe (fMLP) under unprimed and tumor necrosis factor alpha (TNF-alpha)- or interleukin 8-primed conditions. Similarly, LTB4 liberation was significantly reduced in response to fMLP and phorbol myristate acetate in unprimed and TNF-alpha-primed pregnancy PMNs. All major fatty acid classes were altered in the pregnant state. Of these differences in PMNs, oleic acid and alpha-linolenic acid showed a significant increase (13 and 26%, respectively) and stearic acid and AA showed a significant decrease (8 and 30%, respectively). The stearic acid, oleic acid, and AA compositions of all cells analyzed correlated with their corresponding changes in serum fatty acid levels. Crossover serum incubations modified both fatty acid profiles and the PMN respiratory burst accordingly, while individual fatty acid incorporation studies highlighted the importance of polyunsaturated fatty acids for NADPH oxidase efficiency. These findings indicate that the attenuation of PMN function in pregnancy may originate from a reduction in the available pool of cellular fatty acids. Furthermore, this reduction arises as a direct result of a pregnancy-induced shift in circulating fatty acids from polyunsaturated to monounsaturated forms.
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PMID:Significance of fatty acids in pregnancy-induced immunosuppression. 1039 68

Spreading depression is a wave of sustained depolarization challenging the energy metabolism of the cells without causing irreversible damage. In the ischaemic brain, sreading depression-like depolarization contributes to the evolution of ischaemia to infarction. The depolarization is propagated by activation of N-methyl-D-aspartate receptors, but changes in signal transduction downstream of the receptors are not known. Because protein phosphorylation is a general mechanism whereby most cellular processes are regulated, and inhibition of N-methyl-D-aspartate receptors or protein kinase C is neuroprotective, the expression of protein kinase C subspecies in spreading depression was examined. Cortical treatment with KCl induced an upregulation of protein kinase Cdelta and zeta messenger RNA at 4 and 8 h, whereas protein kinase Calpha, beta, gamma and epsilon did not show significant changes. The gene induction was the strongest in layers 2 and 3, and was followed by an increased number of protein kinase Cdelta-immunoreactive neurons. Protein kinase Cdelta and zeta inductions were inhibited by pretreatment with an N-methyl-D-aspartate receptor antagonist, dizocilpine maleate, which also blocked spreading depression propagation, and with dexamethasone, which acted without blocking the propagation. Quinacrine, a phospholipase A2 inhibitor, reduced only protein kinase C5 induction. In addition, N(G)(-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, did not influence protein kinase Cdelta or zeta induction, whereas 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor antagonist, and the cyclo-oxygenase inhibitors indomethacin and diclophenac tended to increase gene expression. The data show that cortical spreading depression induces Ca2(+)-independent protein kinase C subspecies delta and zeta, but not Ca(2+)-dependent subspecies, through activation of N-methyl-D-aspartate receptors and phospholipase A2. Even though the signal pathway is similar to the induction described previously in ischaemia for genes implicated in delayed neuronal death, the gene inductions observed here are not necessarily pathogenetic, but may represent a general reaction to metabolic stress.
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PMID:Spreading depression induces expression of calcium-independent protein kinase C subspecies in ischaemia-sensitive cortical layers: regulation by N-methyl-D-aspartate receptors and glucocorticoids. 1047 63


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