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)

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

Nitric oxide (NO) has been implicated in a number of important brain functions, such as long-term potentiation (LTP) and long-term depression (LTD), and in events associated with neurodegeneration and neuroprotection. In response to brain injury or disease NO production is increased by an inducible enzyme (iNOS), which is only expressed under these conditions. Activated microglia are a major cellular source of iNOS in brain. Due to the important role of iNOS in brain injury and disease, a detailed understanding of intracellular events triggering the expression of iNOS in microglia would facilitate pharmacotherapeutic approaches. It is shown here, that iNOS mRNA, protein and NO product are induced in cultured microglia by lipopolysaccharide (LPS). This induction is reduced by a number of substances elevating intracellular cyclic AMP levels. It is unabated, however, in the presence of substances inhibiting cyclooxygenase-1 and/or cyclooxygenase-2 (e.g., acetyl salicylic acid, SC 58125, L 745337), but is decreased by approx. 50% with PDTC, a scavenger of reactive oxygen intermediates (ROI) that inhibits nuclear factor kappaB (NF-kappaB) activation. Furthermore, inhibitors of protein kinase C (PKC) strongly inhibit iNOS mRNA and protein induction. PKC, therefore, constitutes a major second messenger component (besides NF-kappaB) in the signaling pathway regulating iNOS expression in microglia.
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PMID:Protein kinase C-mediated regulation of inducible nitric oxide synthase expression in cultured microglial cells. 991 92

The only treatment of patients with acute ischemic stroke is thrombolytic therapy, which benefits only a fraction of stroke patients. Both human and experimental studies indicate that ischemic stroke involves secondary inflammation that significantly contributes to the outcome after ischemic insult. Minocycline is a semisynthetic second-generation tetracycline that exerts antiinflammatory effects that are completely separate from its antimicrobial action. Because tetracycline treatment is clinically well tolerated, we investigated whether minocycline protects against focal brain ischemia with a wide therapeutic window. Using a rat model of transient middle cerebral artery occlusion, we show that daily treatment with minocycline reduces cortical infarction volume by 76 +/- 22% when the treatment is started 12 h before ischemia and by 63 +/- 35% when started even 4 h after the onset of ischemia. The treatment inhibits morphological activation of microglia in the area adjacent to the infarction, inhibits induction of IL-1beta-converting enzyme, and reduces cyclooxygenase-2 expression and prostaglandin E(2) production. Minocycline had no effect on astrogliosis or spreading depression, a wave of ionic transients thought to contribute to enlargement of cortical infarction. Treatment with minocycline may act directly on brain cells, because cultured primary neurons were also salvaged from glutamate toxicity. Minocycline may represent a prototype of an antiinflammatory compound that provides protection against ischemic stroke and has a clinically relevant therapeutic window.
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PMID:A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. 1055 49

Spreading depression (SD) is a wave of sustained depolarization challenging the energy metabolism of the cells without causing irreversible damage. However, brain injury, especially focal ischemic stroke, triggers SD-like waves, which in the vicinity of the original damage site contribute to enlargement of the dying brain tissue. Brain injury induces expression of several genes, which are thought to play a role in neuronal death, and therefore represent potential targets for therapy. One such gene is cyclooxygenase-2 (COX-2), an inducible prostaglandin and superoxide producing enzyme. Here we review our recent studies on the regulation of COX-2 in SD.
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PMID:Spreading depression-induced cyclooxygenase-2 expression in the cortex. 1090 26

Spreading depression (SD) is a wave of sustained depolarization challenging the energy metabolism of cells without causing irreversible damage. SD is a major mechanism of gene induction that takes place in cortical injury, including ischemia. We studied the role of oxygen radicals in SD-induced c-fos and cyclooxygenase-2 (COX-2) induction using transgenic (Tg) mice that overexpress copper/zinc-superoxide dismutase (SOD1). The frequency, amplitude and duration of SD waves were similar in the Tg mice and wild-type littermates. c-fos and COX-2 mRNAs were strongly induced 1 and 4 h after SD. The induction of both genes was slightly but significantly less at 4 h in the Tg mice. The results indicate that even a mild, noninjurious metabolic stimulation increases the concentration of oxygen radicals to the level that contributes to gene expression.
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PMID:Spreading depression-induced expression of c-fos and cyclooxygenase-2 in transgenic mice that overexpress human copper/zinc-superoxide dismutase. 1097 46

Cytokines act on the brain to induce fever and behavioural depression after infection. Although several mechanisms of cytokine-to-brain communication have been proposed, their physiological significance is unclear. We propose that behavioural depression is mediated by the vagus nerve activating limbic structures, while fever would primarily be due to humoral mechanisms affecting the preoptic area, including interleukin-6 (IL-6) action on the organum vasculosum of the laminae terminalis (OVLT) and induction of prostaglandins. This study assessed the effects of subdiaphragmatic vagotomy in rats on fever, behavioural depression, as measured by the social interaction test, and Fos expression in the brain. These responses were compared with induction of the prostaglandin-producing enzyme cyclooxygenase-2 and the transcription factor Stat3 that translocates after binding of IL-6. Vagotomy blocked behavioural depression after intraperitoneal injection of recombinant rat IL-1beta (25 microg/kg) or lipopolysaccharide (250 microg/kg; LPS) and prevented Fos expression in limbic structures and ventromedial preoptic area, but not in the OVLT. Fever was not affected by vagotomy, but associated with translocation of Stat3 in the OVLT and cyclooxygenase-2 induction around blood vessels. These results indicate that the recently proposed vagal link between the immune system and the brain activates limbic structures to induce behavioural depression after abdominal inflammation. Although the vagus might play a role in fever in response to low doses of LPS by activating the ventromedial preoptic area, it is likely to be overridden during more severe infection by action of circulating IL-6 on the OVLT or prostaglandins induced along blood vessels of the preoptic area.
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PMID:The vagus nerve mediates behavioural depression, but not fever, in response to peripheral immune signals; a functional anatomical analysis. 1112 54

In infectious diseases and during inflammation, anorexia, loss of body weight, malaise, fatigue and depression are induced. These symptoms are correctively called 'sickness behaviors', and the central actions of cytokines play a role in their induction. The loss of body weight in cancer cachexia is also a result of development of sickness behaviors. It has been reported that the administration of NSAID ibuprofen to patients with cancer cachexia improves the loss in body weight. We studied the effect of NSAID on the loss of body weight by using rodent sickness behavior models. We have reported that sickness behaviors such as anorexia, decrease in body weight, and loss of locomotor activity are induced in concanavalin A (Con A)-induced mouse hepatitis and carbon tetrachloride-induced rat hepatitis. Zaltoprofen is a non-steroidal anti-inflammatory drug (NSAID) causes potent inhibition of cyclooxygenase-2 with fewer side effects on the gastrointestinal tract. Zaltoprofen improves the loss in body weight in both Con A-treated mice and carbon tetrachloride-treated rats. These results suggest the possible application of zaltoprofen for the treatment of sickness behaviors including loss of body weight occurring in cancer cachexia.
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PMID:NSAID zaltoprofen improves the decrease in body weight in rodent sickness behavior models: proposed new applications of NSAIDs (Review). 1189 29

The involvement of cyclooxygenase-2 (COX-2)-derived products and superoxide anion in the effect of lipopolysaccharide in noradrenaline (NA)-induced contraction was investigated in small mesenteric arteries (SMA) from normotensive, Wistar Kyoto (WKY), and spontaneously hypertensive (SHR) rats. In WKY, lipopolysaccharide (10 microg/ml, 1 and 5 h) only inhibited the NA response (0.1-30 microM) in the presence of dexamethasone (1 microM), indomethacin (10 microM), the selective COX-2 inhibitor, NS 398 (10 microM), and the TXA(2)/PGH(2) receptor antagonist, SQ 29,548 (10 microM) but not of superoxide dismutase (SOD, 100 U/ml). In SHR, lipopolysaccharide inhibited the NA response by itself; this inhibition was potentiated by dexamethasone, indomethacin, NS 398, SQ 29,548 and SOD. The effect of lipopolysaccharide plus indomethacin, NS 398 or SQ 29,548 was higher in SMA from WKY than SHR only after 1 h lipopolysaccharide incubation. N(G)-nitro-L-arginine methyl ester (100 microM) and endothelium removal abolished the indomethacin-induced potentiatory effect of lipopolysaccharide in both strains. Endothelium removal also abolished the SOD potentiatory effect in SMA from SHR. Lipopolysaccharide increases COX-2 expression to a similar level in both strains and iNOS expression in a greater extent in SHR; these increases were reduced by dexamethasone. These results indicate: 1) lipopolysaccharide induces the endothelial production of contractile prostanoids from COX-2 in SMA, probably to compensate the increase in NO from iNOS; 2) the production of prostanoids in the presence of lipopolysaccharide seems to be greater in normotensive than hypertensive rats only after lipopolysaccharide short incubation times; 3) endothelial production of O(2)(.-) contributes to counteract depression of NA contraction caused by lipopolysaccharide only in SHR.
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PMID:Hypertension alters the participation of contractile prostanoids and superoxide anions in lipopolysaccharide effects on small mesenteric arteries. 1217 94

Cyclooxygenase-2 (COX-2) plays an important role in the development of injury during cerebral ischemia and inhibition of its activity can reduce infarct size. COX-2 expression during acute ischemia is caused by activation of post-synaptic glutamate receptors, which occurs during spreading depression and ischemic depolarization. Both of these phenomena cause a reduction in the apparent diffusion coefficient of water (ADC), which can be detected with diffusion-weighted magnetic resonance imaging. The reduction is believed to be caused by cellular swelling that occurs as cells depolarize. The goal of this work was to determine the spatial relationship between cyclooxygenase-2 mRNA (cox-2) expression, c-fos mRNA expression and ADC reduction during acute focal cerebral ischemia. Adult rats were subjected to either 30- or 60-min permanent occlusion of the middle cerebral artery. A 2-Tesla scanner was used to acquire diffusion-weighted echo-planar images throughout the ischemic period, which were used to calculate ADC maps. Cox-2 and c-fos mRNA were detected with (35)S in situ hybridization. The results indicate that, for rats subjected to 60-min ischemia, cox-2 was observed in superficial layers of cortex, where transient ADC reduction and c-fos expression were observed. The same was true for most rats subjected to 30-min ischemia. However, in a small number of rats of the 30-min group, cox-2 mRNA expression was observed in regions exhibiting transient and persistent ADC reduction with no c-fos expression. The results suggest that cox-2 mRNA expression during acute MCA occlusion is caused by either or both spreading depression and transient ischemic depolarization.
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PMID:Cyclooxygenase-2 mRNA expression is associated with c-fos mRNA expression and transient water ADC reduction detected with diffusion MRI during acute focal ischemia in rats. 1253 84

Long-term potentiation (LTP) and long-term depression (LTD) are two forms of activity-dependent synaptic plasticity that are thought to be involved in learning and memory. Evidence has shown that cyclooxygenase-2 (COX-2), an enzyme that converts arachidonic acid to prostaglandins, is expressed in postsynaptic dendritic spines and is regulated by synaptic activity. COX-2 inhibition has been shown to directly attenuate LTP in the dentate gyrus of the hippocampus. Also recently the p38 MAP kinase cascade, a pathway utilised by cells for COX-2 expression, has been implicated in LTD induction in the CA1 region of the hippocampus. Here we demonstrate for the first time a direct role for COX-2 and p38 MAP kinase in LTD and confirm the inhibitory role of COX-2 in LTP in the rat dentate gyrus. Perfusion of the COX-2 inhibitor NS-398 (1 micro M) 60 min before tetanic stimulation resulted in an attenuation of LTD (84+/-5%, n=5 compared to controls of 57+/-7%, n=6, P<0.05). Prolonged exposure (2 h) to NS-398 (1 micro M) resulted in a significant reduction in LTP (71+/-8%, n=5, P<0.01 compared to controls of 170+/-11%, n=5 at 60 min post HFS). The p38 MAPK inhibitor, SB220025 (250 nM) significantly attenuated LTD (88+/-5%, n=7; P<0.01 compared to vehicle controls at 60 min, 56+/-5%, n=6) but had no significant effect on LTP. Both NS-398 and SB220025 had no significant effect on the isolated NMDA-mediated EPSP. These data demonstrate a role for COX-2 and p38 MAPK in LTD in the dentate gyrus in vitro that is independent of NMDA receptor activation.
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PMID:A role for COX-2 and p38 mitogen activated protein kinase in long-term depression in the rat dentate gyrus in vitro. 1260 95


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