Fluoxetine, not Paroxetine, Ameliorates Vascular Dysfunctions in Diabetic/Depressed Rats via Pro-inflammatory Cytokines 'MCP-1 and TNF-α' and Metabolic Mechanisms

Multiple evidences indicate that depression is more prevalent in diabetic subjects than in the general population and increases the risk of vascular complications in diabetes too. Nevertheless, little information is available on vascular effects of antidepressant drugs in diabetes. The current study used diabetic rats exposed to chronic restraint stress (CRS), an animal model of depression, to investigate the vascular effects of selective serotonin reuptake inhibitors 'fluoxetine (FLU) and paroxetine (PAR)'; in diabetic/depressed subjects. Possible role of proinflammatory cytokines, monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) and metabolic changes were investigated as well. For induction of type II diabetes (DM), rats were exposed to high fat diet and streptozotocin (35 mg/Kg, i.p.). Diabetic/depressed rats exhibited endothelial dysfunction, confirmed by a significant increase in aortic ring phenylephrine contractile response and Intima/Media ratio as well as a decrease in acetylcholine-dependent relaxation, and these effects were associated with significant elevation of MCP-1 and TNF-α levels in serum and aortic tissue and metabolic dysfunctions, evidenced by alterations in blood glucose, insulin, lipids and insulin sensitivity. Chronic treatment with FLU (10 mg/kg/day, i.p.) significantly ameliorated the DM/CRS-induced endothelial and metabolic dysfunctions that were worsened by PAR (10 mg/kg/day, i.p.). Moreover, FLU, not PAR reduced the elevated levels of MCP-1 and TNF-α. The present results suggest that chronic treatment with FLU improves vascular dysfunctions in diabetic/depressed rats, partially via its potent anti-inflammatory effect and other via reversing metabolic abnormalities. Conversely, PAR aggravated these diabetic complications. Nevertheless, the antidepressant effect of both drugs appeared to be attenuated in diabetic/depressed rats