The Effects of Fluoxetine versus Imipramine on Vascular Abnormalities and Toll Like Receptor-4 Gene Expression in Diabetic and Non-diabetic Rats Exposed to Chronic Stress

Abstract

The concurrence of depression and diabetes is a serious problem. Among people with diabetes, whose risk of depression is 50–100% greater than the general population;depression is associated with higher complication and mortality rates. Moreover, depression may impair control of glycemia and treatment compliance, as well as increasing the risk of vascular complications indiabetes. On the other hand, the response to antidepressants has been reported to be altered in diabetics. A report at the annual meeting of the American Psychiatric Association indicated that the total burden of cardiovascular risk factors in a patient with major depressive disorder is an independent predictor of lack of response to antidepressant therapy with fluoxetine. Treatment with antidepressants has also been reported to affect glucose homeostasis in diabetic individuals. Although diabetes risk is elevated for the major antidepressant classes, the risks posed by individual medications may vary widely. Indeed, several studies indicated that the effect of selective serotonin reuptake inhibitors (SSRIs) on glycemic control is quite controversial. Long-term treatment with paroxetine and fluvoxamine has been reported to carry an increased diabetes risk while elevated risk was not associated with long-term use of fluoxetine, citalopram, or sertraline. In contrast, a hypoglycemic effect was reported by a study involving fluoxetine or paroxetine while other studies failed to confirm this finding and still others noted a worsening of glycemic control.

Vascular disease is the most important complication of both type 1 and type 2 diabetes, with both micro- and macrovascular disease underlying most of the death and disability observed in diabetic patients. Endothelial dysfunction is a cardinal feature of both types of diabetes, and is believed to be involved in the aetiology and pathophysiology of diabetic vasculopathy. On the other hand, a considerable amount of evidence has shown that psychosocial factors play an important role in the etiology and progression of certain cardiovascular diseases such as atherosclerosis. Previous studies reported that apolipoprotein E knockout mice subjected to chronic mild stress (CMS) demonstratedmarkedly increased aortic atherosclerosis that were associated with significant increases in levels of expression of Toll Like Receptor-4, nuclear factor κB (NF-κB), and TNF-α. TLR-4 is expressed on virtually all human cells and binds a wide spectrum of exogenous and endogenous ligands and is involved in innate immune responses to various infectious agents and stressors. Evidence is accumulating that TLR-4 plays an important role in the pathogenesis of atherosclerosis. Activation of TLR-4 results in NF-κB activation and subsequent induction of proinflammatory cytokines e.g TNF-α. Also, a key role for TLR-4 in the mechanism whereby diet-induced obesity induces vascular inflammation and insulin resistance was suggested. Thus, there is a plausible linkage of TLR-4 to the production of proinflammatory cytokines e.g. TNF-α, which, in turn, contribute to vascular dysfunction associated with depression and diabetes type II.