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)

The prostaglandin G/H synthase enzymes, commonly termed COX-1 and COX-2, differ markedly in their responses to regulatory stimuli and their tissue expression patterns. COX-1 is the dominant source of "housekeeping" prostaglandins, whereas COX-2 synthesizes prostaglandins of relevance to pain, inflammation, and mitogenesis. Despite these distinctions, the two enzymes are remarkably conserved, and their subcellular distributions overlap considerably. To address the functional interchangeability of the two isozymes, mice in which COX-1 is expressed under COX-2 regulatory elements were created by a gene targeting "knock-in" strategy. In macrophages from these mice, COX-1 was shown to be lipopolysaccharide-inducible in a manner analogous to COX-2 in wild-type macrophages. However, COX-1 failed to substitute effectively for COX-2 in lipopolysaccharide-induced prostaglandin E2 synthesis at low concentrations of substrate and in the metabolism of the endocannabinoid 2-arachidonylglycerol. The marked depression of the major urinary metabolite of prostacyclin in COX-2 null mice was only partially rescued by COX-1 knock-in, whereas the main urinary metabolite of prostaglandin E2 was rescued totally. Replacement with COX-1 partially rescued the impact of COX-2 deletion on reproductive function. The renal pathology consequent to COX-2 deletion was delayed but not prevented, whereas the corresponding peritonitis was unaltered. Insertion of COX-1 under the regulatory sequences that drive COX-2 expression indicated that COX-1 can substitute for some COX-2 actions and rescue only some of the consequences of gene disruption. Manipulation of COX-2 also revealed a preference for coupling with distinct downstream prostaglandin synthases in vivo. These mice will provide a valuable reagent with which to elucidate the distinct roles of the COX enzymes in mammalian biology.
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PMID:Targeted cyclooxygenase gene (ptgs) exchange reveals discriminant isoform functionality. 1711 Mar 78

Acute hypoxia increases ventilatory drive in conscious animals, resulting in tachycardia. Sustained hypoxia changes the initial chemoreflex ventilatory increase to secondary ventilatory depression, which then evokes a gradual secondary heart rate (HR) reduction. Prostacyclin (PGI(2)) release is known to potentiate alpha(2)-adrenoreceptor (alpha(2)-AR) mediated inhibition of sympathoactivation during ischaemia and hypoxia. We examined whether alpha(2)-AR mediated sympathoinhibition was responsible for limiting hypoxic heart rate increases during initial sympathoactivation, and subsequent secondary HR depression, and if PGI(2) is required for sympathoinhibition of HR. The responses of unrestrained PGI(2) synthase deficient (PGID) and wild type (WT) mice to acute hypoxia (10% O(2) for 30 min) were investigated by simultaneous telemetry, whole body plethysmography and open-flow respirometry. PGID mice exhibited potentiated .V(E) (p < 0.007) after intraperitoneal vehicle injection (n = 8), but not so HR responses compared to WT mice during sustained hypoxia. Idazoxan (alpha(2)-AR antagonist, i.p. bolus 3 mg/kg) pretreatment did not change hypoxic ventilatory response in either group, but significantly elevated hypoxic HR in WT mice only (p < 0.013). Sodium meclofenamate (cyclooxygenase inhibition, i.p. bolus 25 mg/kg) pretreatment eliminated the potentiated .V(E) of PGID and caused significant basal hypotension that led to a transient hypertensive response to hypoxia. From these results, we suggest that alpha(2)-AR activation is required for coupling HR to central inspiratory drive during acute hypoxia, and that PGI(2) is required to enhance the inhibition of sympathoactivation.
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PMID:Alpha2-adrenoreceptor mediated sympathoinhibition of heart rate during acute hypoxia is diminished in conscious prostacyclin synthase deficient mice. 1712 18

Antidepressants have an antiproliferative effect in some cell lines. Depression may be associated with activation of some pro-inflammatory cytokines. Therefore, we evaluated the ex-vivo immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) in T cells. We found that the SSRIs, paroxetine and sertraline decreased T-cell viability with IC50 around 10 microM. The inhibition obtained with exposure to the SSRIs was more pronounced than that achieved with dexamethasone. Moreover, these SSRIs inhibit the secretion of the TH1 factor-tumor necrosis factor(TNF)alpha from the cells. On the molecular level, the SSRIs suppressed signal transducer and activator of transcription 3 (Stat3) and cyclooxygenase(Cox)2 protein expression. The inhibitory effects were accompanied by alterations in gene expression as assessed in the gene array. These findings reveal an immunomodulatory effect of the SSRIs paroxetine and sertraline in human T cells. The clinical implications of our findings merit further investigation.
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PMID:Immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) on human T lymphocyte function and gene expression. 1749 75

Serotonin, well known for its role in depression, has been shown to modulate immune responses. Interestingly, the plasma level of serotonin is increased in symptomatic asthmatic patients and the use of anti-depressants, known to reduce serotonin levels, provokes a decrease in asthma symptoms and an increase in pulmonary function. Thus, we tested the hypothesis that serotonin affects alveolar macrophage (AM) cytokine production, altering the cytokine network in the lung and contributing to asthma pathogenesis. AMs were treated with different concentrations of serotonin (10(-11)-10(-9) M) or 5-HT(1) and 5-HT(2) receptor agonists for 2 h prior stimulation. T helper 1 (Th1) and Th2 cytokines, prostaglandin-E(2) (PGE(2)) and nitric oxide (NO) were measured in cell-free supernatants. Serotonin significantly inhibited the production of tumour necrosis factor (TNF) and interleukin (IL)-12, whereas IL-10, NO and PGE(2) production were increased. These immunomodulatory effects of serotonin were mimicked by 5-HT(2) receptor agonist but were not abrogated by 5-HT(2) receptor antagonist, suggesting the implication of other 5-HT receptors. Inhibitors of cyclooxygenase and antibody to PGE(2) abrogated the inhibitory and stimulatory effect of serotonin on TNF and IL-10 production, respectively, whereas NO synthase inhibitor eliminated serotonin-stimulated IL-10 increase. Furthermore, PGE(2) significantly increased AM IL-10 and NO production. These results suggest that serotonin alters the cytokine network in the lung through the production of PGE(2). The reduction of Th1-type cytokine by serotonin may contribute to asthma pathogenesis.
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PMID:Serotonin modulates the cytokine network in the lung: involvement of prostaglandin E2. 1782 43

Cortical spreading depression is an excitatory wave of depolarization spreading throughout cerebral cortex at a rate of 2-5 mm/min and has been implicated in various neurological disorders, such as epilepsy, migraine aura, and trauma. Although sleepiness or sleep is often induced by these neurological disorders, the cellular and molecular mechanism has remained unclear. To investigate whether and how the sleep-wake behavior is altered by such aberrant brain activity, we induced cortical spreading depression in freely moving rats, monitoring REM and non-REM (NREM) sleep and sleep-associated changes in cyclooxygenase (COX)-2 and prostaglandins (PGs). In such a model for aberrant neuronal excitation in the cerebral cortex, the amount of NREM sleep, but not of REM sleep, increased subsequently for several hours, with an up-regulated expression of COX-2 in cortical neurons and considerable production of PGs. A specific inhibitor of COX-2 completely arrested the increase in NREM sleep. These results indicate that up-regulated neuronal COX-2 would be involved in aberrant brain excitation-induced NREM sleep via production of PGs.
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PMID:Up-regulated neuronal COX-2 expression after cortical spreading depression is involved in non-REM sleep induction in rats. 1792 12

Chronic administration to rats of mood-stabilizers that are effective against mania in bipolar disorder, is reported to downregulate markers of the brain arachidonic acid cascade. We hypothesized that chronic administration of lamotrigine, which is used to treat depression and rapid cycling in bipolar disorder, might do so as well. Male CDF rats were administered a therapeutically relevant dose of lamotrigine (10 mg/kg) or vehicle intragastrically once daily for 42 days. Protein levels of isoforms of phospholipase A(2) (PLA(2)) and of cyclooxygenase (COX), and the mRNA level of COX-2, were quantified in the frontal cortex using immunoblotting and RT-PCR, respectively. Compared to vehicle-treated rats, chronic lamotrigine significantly decreased frontal cortex protein and mRNA levels of COX-2 without altering protein levels of the PLA(2) isoforms. Consistent with the hypothesis, lamotrigine and other mood-stabilizers have a common downregulatory action on COX-2 expression in rat brain, which may account in part for their efficacy in bipolar disorder.
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PMID:Chronic administration of lamotrigine downregulates COX-2 mRNA and protein in rat frontal cortex. 1808 Jan 90

Electroconvulsive therapy (ECT) is an effective treatment for depression and other psychiatric disorders. However, the practice of ECT is limited by memory and nonmemory cognitive adverse effects. Technical strategies such as a preference for unilateralover bilateral ECT and low-dose over high-dose stimulation reduce these cognitive adverse effects but may also be associated with lesser treatment efficacy or slower treatment response. This article therefore reviews the use of psychopharmacological agents in the attenuation of ECT-induced cognitive deficits with 2 objectives: the identification of implicated mechanisms and the identification of putative efficacy in both animal and human studies. Drugs examined include N-methyl-d-aspartate receptor antagonists, cyclooxygenase inhibitors, calcium channel blockers, cholinesterase inhibitors, glucocorticoid receptor antagonists, thyroid hormones, opioid antagonists, NO donors, nootropic agents, and other medications. Although the clinical data at present are sparse and inconsistent, many recently opened lines of research improve our understanding of the mechanisms involved as well as suggest possible avenues for the testing of new treatments with the potential to attenuate the cognitive adverse effects of ECT.
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PMID:Pharmacological attenuation of electroconvulsive therapy--induced cognitive deficits: theoretical background and clinical findings. 1837 37

7alpha-Hydroxy-DHEA, 7beta-hydroxy-DHEA and 7beta-hydroxy-EpiA are native metabolites of dehydroepiandrosterone (DHEA) and epiandrosterone (EpiA). Since numerous steroids are reported to interfere with inflammatory and immune processes, our objective was to test the effects of these hydroxysteroids on prostaglandin (PG) production and related enzyme gene expression. Human peripheral blood monocytes were cultured for 4 and 24 h in the presence of each of the steroids (1-100 nM), with and without addition of TNF-alpha (10 ng/mL). Levels of PGE(2), PGD(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) were measured in the incubation medium, and cell content of cyclooxygenase (COX-2), and PGE and PGD synthases (m-PGES1, H-PGDS, L-PGDS), and peroxisome proliferator activated receptor (PPAR-gamma) was assessed by quantitative RT-PCR and Western blots. Addition of TNF-alpha resulted in elevated PG production and increased COX-2 and m-PGES1 levels. Among the three steroids tested, only 7beta-hydroxy-EpiA decreased COX-2, m-PGES1 and PPAR-gamma expression while markedly decreasing PGE(2) and increasing 15d-PGJ(2) production. These results suggest that 7beta-hydroxy-EpiA is a native trigger of cellular protection through simultaneous activation of 15d-PGJ(2) and depression of PGE(2) synthesis, and that these effects may be mediated by activation of a putative receptor, specific for 7beta-hydroxy-EpiA.
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PMID:7beta-Hydroxy-epiandrosterone-mediated regulation of the prostaglandin synthesis pathway in human peripheral blood monocytes. 1855 3

Recent clinical trails reported that adjunctive cyclooxygenase (COX)-2 inhibition with celecoxib is beneficial in treating depression. However, another clinical study showed celecoxib did not have inhibitory effect of COX-2 in human brain when given at a therapeutic dose. Therefore, whether celecoxib is exerting its influence through COX inhibition or by some other mechanism remains unclear. The present study further investigated the effect of celecoxib on COX-2 expression, prostaglandin E(2) (PGE2, a major COX-2-mediated inflammatory mediator) concentration and the depressive-like behaviors in rats. Celecoxib was administrated by oral gavage to naive rats (16 mg/kg) or stressed rats (2, 8, 16 mg/kg, respectively) for 21 days, or to stressed rats for a single dose (16 mg/kg). The results showed that 21 days chronic unpredictable stress induced depressive-like behaviors and increased the COX-2 expression and PGE2 concentration in rat brain. Chronic treatments with celecoxib alleviated the depressive-like behavior and reversed the levels of COX-2 expression and PGE2 concentration in stressed rat in a dose-dependent manner. Celecoxib also improved the emotional state and decreased COX-2 expression and PGE2 concentration in naive rats. In addition, a single dose of celecoxib treatment reversed COX-2 expression and PGE2 concentration, but didn't alter the depressive-like behavior in stressed rat. These results suggest that COX-2 enzyme might play a key role in pathophysiology of depression. Furthermore, these data indicate that chronic celecoxib treatment reverse chronic unpredictable stress-induced depressive-like behavior might via reducing COX-2 enzyme in brain, and the selective COX-2 inhibitors could be developed as potential remedies for the management of depression.
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PMID:Chronic treatment with celecoxib reverses chronic unpredictable stress-induced depressive-like behavior via reducing cyclooxygenase-2 expression in rat brain. 1935 23

In this study, we show the crucial roles of lipid signaling in long-term depression (LTD), that is, synaptic plasticity prevailing in cerebellar Purkinje cells. In mouse brain slices, we found that cPLA(2)alpha knockout blocked LTD induction, which was rescued by replenishing arachidonic acid (AA) or prostaglandin (PG) D(2) or E(2). Moreover, cyclooxygenase (COX)-2 inhibitors block LTD, which is rescued by supplementing PGD(2)/E(2). The blockade or rescue occurs when these reagents are applied within a time window of 5-15 min following the onset of LTD-inducing stimulation. Furthermore, PGD(2)/E(2) facilitates the chemical induction of LTD by a PKC activator but is unable to rescue the LTD blocked by a PKC inhibitor. We conclude that PGD(2)/E(2) mediates LTD jointly with PKC, and suggest possible pathways for their interaction. Finally, we demonstrate in awake mice that cPLA(2)alpha deficiency or COX-2 inhibition attenuates short-term adaptation of optokinetic eye movements, supporting the view that LTD underlies motor learning.
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PMID:Lipid signaling in cytosolic phospholipase A2alpha-cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning. 2013 5


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