The link between unpredictable chronic mild stress model for depression and vascular inflammation?

Inflammation has been suggested to be associated with stress-induced depression and cardiovascular dysfunction. Tumor necrosis factor alpha (TNF-α) is a major cytokine in the activation of neuroendocrine, immune, and behavioral responses. In this study, we investigated the effects of infliximab (a TNF-α inhibitor) on endothelium-dependent vascular reactivity, systemic blood pressure, and endothelial nitric oxide synthase (eNOS) immunoreactivity in the unpredictable chronic mild stress (UCMS) model of depression in rats. There was no significant change between all groups in the systemic blood pressure. In UCMS, endothelium-dependent relaxation of the smooth muscle in response to carbachol was significantly decreased with 50 % maximal response (E max) and pD2 values compared with the controls. Infliximab was able to reverse this UCMS effect. Relaxation in response to the nitric oxide (NO) donor sodium nitroprusside and papaverine and KCl-induced contractile responses was similar between groups. In UCMS, decreased expression of eNOS was detected. Moreover, there was no significant change in UCMS + infliximab group with respect to control rats. Our results suggest that tumor necrosis factor-alpha (TNF-α) could be a major mediator of vascular dysfunction associated with UCMS, leading to decreased expression of eNOS.

Chronic administration of infliximab (TNF-α inhibitor) decreases depression and anxiety-like behaviour in rat model of chronic mild stress.

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-α inhibitors in patients with chronic inflammatory diseases. In this study, we evaluated the antidepressant and anxiolytic effects of chronic TNF-α 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-α inhibition reduced depression and anxiety-like behaviour in the CMS model of depression in rats.