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      Effect of the COX-2 Inhibitor Celecoxib on Behavioural and Immune Changes in an Olfactory Bulbectomised Rat Model of Depression

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          Background: The olfactory bulbectomised (OBX) rat model is a chronic model of depression in which behavioural and neuroimmunoendocrine changes are reversed only after chronic antidepressant treatment. The cyclooxygenase 2 (COX-2) inhibitor celecoxib has been shown to improve the depressive symptoms in patients with major depression. Methods: The association between blood and brain immunological and behavioural changes in chronic treatment with COX-2 inhibitor was explored in the OBX rats and their sham-operated controls. Results: The OBX group showed significantly higher locomotor activity than the other groups in the first 5 min in the open field. In the home cage emergence test, the OBX group showed a significantly shorter latency period compared to the sham group (z = –3.192, p = 0.001) but there was no difference between the other three groups. In the hypothalamus, the OBX group had a significantly higher interleukin 1β (IL-1β) concentration than the OBX + celecoxib group (z = –1.89, p = 0.05) as well as a significantly higher IL-10 concentration (z = –1.995, p = 0.046). In the prefrontal cortex, the OBX group showed significantly higher concentrations of tumour necrosis factor α (z = –2.205, p = 0.028) and IL-1β (z = –3.361, p = 0.001) than the OBX + celecoxib group, but a significantly lower concentration of IL-10 (p = –3.361, p = 0.001) than the OBX + celecoxib group. Conclusions: The results of this study supported the potential therapeutic role of the COX-2 inhibitor celecoxib. It is possible that the behavioural changes following the chronic administration of celecoxib to the OBX rats are associated with an attenuation of the increase in the pro-inflammatory cytokines in the brain.

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          Most cited references 41

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          The macrophage theory of depression.

           R.S. Smith (1991)
          Excessive secretion of macrophage monokines is proposed as the cause of depression. Monokines when given to volunteers can produce the symptoms necessary for the Diagnostic and Statistical Manual of Mental Disorders, Third Edition Revised (DSM-III-R) diagnosis of major depressive episode. Interleukin-1 (IL-1) can provoke the hormone abnormalities linked with depression. This theory provides an explanation for the significant association of depression with coronary heart disease, rheumatoid arthritis, stroke and other diseases where macrophage activation occurs. The 3:1 female/male incidence of depression ratio is accounted for by estrogen's ability to activate macrophages. The extraordinary low rate of depression in Japan is consistent with the suppressive effect of eicosapentanoic acid on macrophages. Fish oil is proposed as a prophylaxis against depression and omega-6 fat as a promoter. Infection, tissue damage, respiratory allergies and antigens found in food are some of the possible causes of macrophage activation triggering depression.
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            Neuroimaging studies of mood disorders.

            Neuroimaging studies of major depression have identified neurophysiologic abnormalities in multiple areas of the orbital and medial prefrontal cortex, the amygdala, and related parts of the striatum and thalamus. Some of these abnormalities appear mood state-dependent and are located in regions where cerebral blood flow increases during normal and other pathologic emotional states. These neurophysiologic differences between depressives and control subjects may thus implicate areas where physiologic activity changes to mediate or respond to the emotional, behavioral, and cognitive manifestations of major depressive episodes. Other abnormalities persist following symptom remission, and are found in orbital and medial prefrontal cortex areas where postmortem studies demonstrate reductions in cortex volume and histopathologic changes in primary mood disorders. These areas appear to modulate emotional behavior and stress responses, based upon evidence from brain mapping, lesion analysis, and electrophysiologic studies of humans and/or experimental animals. Dysfunction involving these regions is thus hypothesized to play a role in the pathogenesis of depressive symptoms. Taken together, these findings implicate interconnected neural circuits in which pathologic patterns of neurotransmission may result in the emotional, motivational, cognitive, and behavioral manifestations of primary and secondary affective disorders.
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              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.

              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.

                Author and article information

                S. Karger AG
                September 2007
                21 August 2007
                : 14
                : 2
                : 65-71
                aDepartment of Psychiatry and Neuropsychology, University of Maastricht, Maastricht, The Netherlands; bDepartment of Clinical Biochemistry, University of Antwerpen, Antwerpen, Belgium; cDepartment of Psychiatry, Korea University Medical Centre, Korea University, Ansan, Korea
                107420 Neuroimmunomodulation 2007;14:65–71
                © 2007 S. Karger AG, Basel

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                Page count
                Tables: 3, References: 51, Pages: 7
                Original Paper


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