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

Abstract

Several studies reveal that diabetes doubles the odds of comorbid depression with evidence of a pro-inflammatory state underlying its vascular complications. Indeed, little information is available about vascular effects of antidepressant drugs in diabetes. Method: We investigated the effect of chronic administration of fluoxetine “FLU” and imipramine “IMIP” on behavioral, metabolic and vascular abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS). Results: Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP in a comparable manner. Diabetic and non-diabetic rats exposed to CRS exhibited abnormalities in glucose homeostasis, lipid profile and vascular function, manifested by decreased endothelium-dependent relaxation, increased systolic blood pressure and histopathological atherosclerotic changes. Vascular and metabolic dysfunctions were associated with significant increase in aortic expression of TLR-4, and pro-inflammatory cytokines (TNF-α and IL-1ß). FLU ameliorated these metabolic, vascular and inflammatory abnormalities, while IMIP induced either no change or even worsening of some parameters. Conclusion: FLU has favorable effect over IMIP on metabolic, vascular and inflammatory aberrations associated with DM and CRS in Wistar rats, clarifying the preference of FLU over IMIP in management of comorbid depression in diabetic subjects.

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

“…The results of this work alongside our previously published work [16] showed that the metabolic abnormalities induced by type 2 DM were more prominent with CRS accompanied by decreased body weight gain and increased serum corticosterone levels which indicate the absence of adaptive response to stress. Chronic treatment with FLU and IMIP reversed these changes in a comparable manner.…”

“…In a previous work, we have concluded that TLR-4 and subsequent cytokine production may underlie diabetes and psychological stress associated vascular complications [16]. The results of this work emphasize that TLR-4 activation not only underlies complications but it may be also involved in the pathogenesis of both depression and DM.…”

“…In addition, high glucose and saturated fatty acids noticed with DM have been reported to induce TLR-4 activation [15]. Our previous work has reported increased aortic TLR-4 expression in diabetic rats exposed to chronic restraint stress (CRS) with significant correlation to the development of vascular dysfunction and atherosclerotic changes [16].…”

Effect of Toll‐like receptor 4 on depressive‐like behaviors induced by chronic social defeat stress

“…Fluoxetine is a widely used antidepressant which could reverse depressive-like and anxiety-like behaviors (Habib, Shaker, El-Gayar, & Aboul-Fotouh, 2015;Lehmann et al, 2013;Wang et al, 2014). But there is limited evidence about whether TLR4 is involved in the antidepressant effect of fluoxetine.…”

Toll-like receptor (TLR)-2/4 expression in retinal ganglion cells in a high-glucose environment and its implications

“…Previous studies have shown that TLR expression is elevated in muscles, adipocytes, and B lymphocytes in DM patients. Further genetic studies in Chinese type II DM patients have revealed a correlation between polymorphisms in the TLR-4 gene and disease progression, suggesting the involvement of TLR-2 and TLR-4 in the mediation of both type I and type II DM (Habib et al, 2015;Singh et al, 2015a,b). The function of these two factors in DR and the related mechanism, however, remains unclear.…”