Depression, immunocompetence, and prostaglandins of the E series

Calabrese, Joseph R.; Skwerer, Robert G.; Barna, Barbara P.; Gulledge, A. Dale; Valenzuela, Rafael; Butkus, Antanas; Subichin, Steven; Krupp, Neal E.

doi:10.1016/0165-1781(86)90040-5

Cited by 201 publications

(84 citation statements)

References 22 publications

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“…The hypothesis of a dysfunctional AA cascade in mood disorders (Rapoport and Bosetti 2002) is supported by the finding that the level of PGE 2 is increase in plasma, saliva and cerebrospinal fluid of subjects with major depression (Linnoila et al 1983;Calabrese et al 1986;Nishino et al 1989), and by studies suggesting an association between bipolar disorder and genes involved in the cascade such as prostaglandin receptors, phospholipase A 2 and COX-2 (Bennett and Horrobin 2000).…”

Section: Discussionmentioning

confidence: 74%

Valproic acid down‐regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase‐1 and ‐2 in rat brain

Bosetti

Weerasinghe

Rosenberger

et al. 2003

Journal of Neurochemistry

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Sodium valproate, a mood stabilizer, when chronically administered to rats (200 mg/kg i.p. daily for 30 days) significantly reduced the brain protein levels of cyclooxygenase (COX)-1 and COX-2, without altering the mRNA levels of these enzymes. COX activity was decreased, as were the brain concentrations of 11-dehydrothromboxane B 2 and prostaglandin E 2 (PGE 2 ), metabolites of arachidonic acid (AA) produced via COX. In contrast, the brain protein level of 5-lipoxygenase and the concentration of its AA metabolite leukotriene B 4 were unchanged. In view of published evidence that lithium chloride administered chronically to rats, like chronic valproate, reduces AA turnover within brain phospholipids, and that lithium post-transcriptionally down-regulates COX-2 but not COX-1 protein level and enzyme activity, these observations suggest that mood stabilizers generally modulate the release and recycling of AA within brain phospholipids, and the conversion of AA via COX-2 to PGE 2 and related eicosanoids. If targeting this part of the 'AA cascade' accounts for their therapeutic action, non-steroidal antiinflammatory drugs or selective COX-2 inhibitors might prove effective in bipolar disorder.

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Section: Discussionmentioning

confidence: 74%

Valproic acid down‐regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase‐1 and ‐2 in rat brain

Bosetti

Weerasinghe

Rosenberger

et al. 2003

Journal of Neurochemistry

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“…Increased levels of PGE 2 have indeed been observed in CSF, in serum and in saliva of depressed patients. [134][135][136] In vitro studies likewise show an increased PGE 2 secretion from lymphocytes of depressed patients compared with healthy controls. 102 Twenty years ago, it was suggested that antidepressants inhibit PGE 2 .…”

Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 94%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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“…10 Increased PGE 2 in the saliva, the serum and the cerebrospinal fluid of depressed patients has previously been described. [11][12][13][14] According to the stimulating effect of PGE 2 on IL-6, most of the studies dealing with IL-6 report a marked increase of IL-6 in vitro production 15 or serum levels in depressed patients. 16,17 On the other hand, it was shown that tricyclic antidepressants and selective serotonin reuptake inhibitors attenuate the PGE 2 -synthesis, probably via inhibition of pro-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine

et al. 2006

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Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E 2 (PGE 2 ), have repeatedly been described in major depression (MD). As cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE 2 production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib. In a prospective, double-blind, add-on study, 40 patients suffering from an acute depressive episode were randomly assigned to either reboxetine and celecoxib or to reboxetine plus placebo. After a wash-out period, 20 patients received 4-10 mg reboxetine plus placebo and 20 received reboxetine plus 400 mg celecoxib for 6 weeks. The treatment effect was calculated by analysis of variance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or reboxetine dose or plasma levels. Over 6 weeks, both groups of patients showed significant improvement in scores of the Hamilton Depression Scale. However, the celecoxib group showed significantly greater improvement compared to the reboxetine-alone group. Additional treatment with celecoxib has significant positive effects on the therapeutic action of reboxetine with regard to depressive symptomatology. Moreover, the fact that treatment with an anti-inflammatory drug showed beneficial effects on MD indicates that inflammation is related to the pathomechanism of the disorder, although the exact mechanisms remain to become elucidated.

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Depression, immunocompetence, and prostaglandins of the E series

Cited by 201 publications

References 22 publications

Valproic acid down‐regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase‐1 and ‐2 in rat brain

Valproic acid down‐regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase‐1 and ‐2 in rat brain

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine

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