Chronic Administration of Infliximab (TNF‐α Inhibitor) Decreases Depression and Anxiety‐like Behaviour in Rat Model of Chronic Mild Stress

Abstract

Pro-inflammatory cytokines have been proposed to be associated with the pathogenesis of depression. Consistent with this notion, several clinical observations have suggested the antidepressant efficacy of TNF-a inhibitors in patients with chronic inflammatory diseases. In this study, we evaluated the antidepressant and anxiolytic effects of chronic TNF-a inhibitor (infliximab, 5 mg/kg, i.p., weekly) administration in the chronic mild stress (CMS) model of depression. Rats were divided into three groups: saline-control (no stress), saline-CMS, and infliximab-CMS. Rats in the latter two groups were exposed to CMS for 8 weeks. Saline (former two groups) or infliximab was injected weekly during this period. After CMS, total locomotor activity, anxiety-like behaviour and depression-like behaviours were evaluated using automated locomotor activity cage, elevated plus maze (EPM), and sucrose preference (SPT) and forced swimming (FS) tests, respectively. As expected, the saline-CMS group exhibited higher depression-like behaviours in FS and SPT tests compared with the saline-control group. There were no differences between these two groups in terms of the anxiety-like behaviour or total locomotor activity. Infliximab reduced the depression-like behaviour of CMS rats compared with saline-CMS group, and anxiety-like behaviour of CMS rats compared with saline-CMS and saline-control groups. Our findings suggest that chronic and systemic TNF-a inhibition reduced depression and anxiety-like behaviour in the CMS model of depression in rats.Various hypotheses have been proposed concerning the neurobiology of depression, each capturing a different aspect(s) of this disorder. These accounts include the disturbance of the monoamine system and HPA axis, neurodegeneration and decreased neurogenesis, and the dysregulation of immune system functions [1][2][3][4]. Among these inter-related pathological processes, the inflammation hypothesis constitutes a relatively recent account of depression [1,3,5]. Results of meta-analytic studies that focused on the relation between depression and immune system have indeed revealed bidirectional interactions between the pro-inflammatory cytokines (TNF-a, IL-6, IL-1) and major depression [6,7]. Specifically, an increasing number of studies have shown that pro-inflammatory cytokines/cytokine inducers lead to depressive symptoms [8-10], antidepressants change the levels of anti-/pro-inflammatory cytokines [11][12][13][14], levels of pro-inflammatory cytokines rise in major depression with/without additional chronic disease [6,7,15] and that depression often accompanies inflammatory disorders [16][17][18].Despite these positive findings, the antidepressant efficacy of pharmacological agents targeting pro-inflammatory cytokines has not been extensively investigated. Lack of studies on this topic is likely due to the novelty of these biological agents in clinical practice and the impermeability of the blood-brain barrier to these agents. On the other hand, the notion regarding the complete ind...

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior

“…For example, central administration of TNFα induced depression-like behaviors in the forced swimming test and tail suspension test (Kaster et al, 2012), while treatment with the TNFα inhibitor infliximab and targeted deletion of TNF receptors had antidepressant effects in mice (Simen et al, 2006;Karson et al, 2013). In agreement with previous studies, we found that administration of TNFα inhibitors reduced by ~20~30% the number of mice that developed learned helplessness, suggesting that stress-induced TNFα contributes to learned helplessness.…”

“…Administration of TNFα inhibitors tended to reduce the number of mice that developed learned helplessness, as 45% of the TNFα inhibitor-treated mice and 55% of the etanercepttreated mice exhibited learned helplessness ( Figure 9A). This supports previous reports that inhibiting TNFα exerts antidepressant properties in mouse models of depression (Karson et al, 2013;Simen et al, 2006: Kaster et al, 2012, but also demonstrates that inhibiting TNFα only modestly reduces the induction of learned helplessness depression-like behavior.…”

A review of the relationship between proinflammatory cytokines and major depressive disorder

“…In addition, TNF antagonism had no significant effect on study participants as a whole when not accounting for inflammatory biomarkers. These results are further supported by a study that demonstrated similar effects of Infliximab on mildly stressed rats including decreased depression and anxiety-like behavior when compared to controls and saline administration (Karson et al, 2013). All in all, these findings raise the possibility of TRD populations who could be uniquely responsive to antiinflammatory intervention, thus suggesting the need for appropriate screenings and treatment.…”

Role of Adiposity-Driven Inflammation in Depressive Morbidity

“…In support of this notion, infliximab was found to reduce depressive symptoms in rodent models of depression (Karson et al, 2013;Liu et al, 2015) as well as in humans suffering from major depression and exhibiting higher level of circulating CRP . Interestingly, these patients were also those who exhibited higher BMI.…”