Behavioural, metabolic, and endothelial effects of the TNF-α suppressor thalidomide on rats subjected to chronic mild stress and fed an atherogenic diet

Abstract

There is accumulating evidence suggesting that depression is a risk factor for cardiovascular diseases. This study aimed to examine the hypothesis that the proinflammatory cytokine TNF-α would partially explain the link between depression and atherosclerotic endothelial changes. Rats were distributed among 6 groups: (i) control group; (ii) group subjected to chronic mild stress (CMS); (iii) group fed a cholesterol-cholic acid-thiouracil (CCT diet); and (iv) CMS group fed the CCT diet and treated with the vehicle for 8 weeks. The last 2 groups were subjected to CMS-CCT and received thalidomide (THAL) or imipramine (IMIP). Rats were assessed behaviorally (sucrose preference, open field, and forced-swimming tests). TNF-α protein was assessed from the serum, aorta, and liver. Aortic TNF-α gene expression (assessed using RT-PCR), serum lipid profile, and insulin levels were measured. Endothelial function was assessed in isolated aortic rings. The THAL and IMIP groups showed ameliorated CMS-CCT-related behavioral changes. CMS-CCT-induced metabolic and endothelial dysfunctions were improved in the THAL group but were worsened in the IMIP group. RT-PCR showed a significant reduction of aortic TNF-α mRNA expression in the THAL and IMIP treatment groups. These data paralleled the findings for aortic immunohistochemistry. The THAL group, but not the IMIP group, showed improved CMS-CCT-induced changes in the vascular reactivity of the aortic rings. Thus, TNF-α provides a target link between depression, metabolic syndrome, and endothelial dysfunction. This could open a new therapeutic approach to address the comorbidities of depression.

The Effects of Antidepressants “Fluoxetine and Imipramine” on Vascular Abnormalities and Toll Like Receptor-4 Expression in Diabetic and Non-Diabetic Rats Exposed to Chronic Stress

“…Ananloo et al [ 42 ] reported increased serum total cholesterol, triglyceride and body weight in depressive patients treated with imipramine. Indeed, previous reports revealed imipramine-induced dyslipidemia, insulin resistance and endothelial dysfunction in CMS model [ 53 ], but this is the first study showing this observation in CRS paradigm.…”

Biochemical Studies of Hippocampal Gene Expression of Brain-Derived Neurotropic Factor and Toll-Like Receptor-4 in Diabetic Rats Exposed to Chronic Stress: Effects of Antidepressant Drugs

“…Literature data show that the chronic IMIP treatment improved chronic stress/ high fat diet-related behavioral changes [31].…”

Off-Target Effects of Antidepressants on Vascular Function and Structure

“…In another study, imipramine did not reduce the expression of the chemokine IP-10 and of three mitogen-activated protein kinase (MAPK) pathways, in Th1 LPS-stimulated human monocytes [ 43 ]. Importantly, imipramine impaired acetylcholine-mediated aortic relaxation despite decreasing TNF-α mRNA levels in the aorta of male Wistar rats on a high fat diet [ 59 ].…”