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

Mitigation of Delayed Sodium Hypochlorite-Induced Lung Injury by Phosphodiesterase Enzyme Inhibitors (PDEIs), Pentoxifylline and Theophylline, in Guinea Pigs

Sodium hypochlorite (NaOCI) is widely used as an industrial material as well as an ingredient in household cleaning products. Exposure to high concentrations of NaOCl, a powerful oxidant, results in acute lung injury that may proceed to delayed airway hyper responsiveness and remodeling. The present study aims at investigating the effects of two nonselective PDEIs, pentoxifylline ‘PTX’ and theophylline ‘THEO‘, versus dexamethasone ‘DEX’ on delayed airway functional and histopathological injury induced by NaOClinhalation in guinea pigs. Forty-eight guinea pigs were classified into 8 groups; 2 groups (control, 4% NaOClinhalation for 20 min) and another 6 groups were exposed to NaOCl and administrated intraperitoneally vehicle, PTX (50 mg/kg/day), THEO (50 mg/kg/day), DEX (20 mg/kg/day), PTX+DEX or THEO+DEX for 3 weeks. Guinea pigs were assessed for airway functional, biochemical and histopathological dysfunctions. Treatment with PENT or THEO, as monotherapy or in combination with DEX, reduced airway resistance and bronchial reactivity to methacholine. Similar findings were noticed with inflammatory markers such as total cell count, neutrophil percentage and TNF-α in bronchoalveolar lavage and lung myeloperoxidase activity and neutrophil infiltration. These data were parallel to lung histopathology and Aschorft fibrosis score that were improved in treatment groups. PENT, but not THEO or DEX could ameliorate oxidative stress biomarkers, malondialdehyde and superoxide dismutase, in lungs. Co-administration of PENT or THEO with DEX improved the effect of DEX on NaOCl-induced airway injury. In conclusion, ‘PENT and THEO’ are effective in mitigation of delayed NaOCl-induced lung injury in guinea pigs and if these findings were to translate into actual clinical benefit, they might provide a suitable alternative to corticosteroids or at least, reduce its dose needed in management of NaOCl and chlorine-induced lung toxicity

Effects of fluoxetine (FLU) and imipramine (IMIP) on lipid profile and glucose homeostasis in non-diabetic and diabetic rats exposed to chronic restraint stress (CRS).

<p>Data are mean±SEM (n = 6).</p><p>*P<0.05</p><p>**P<0.01</p><p>***P<0.001 vs control group;</p><p>^#P<0.05</p><p>^##P<0.01</p><p>^###P<0.001 vs. CRS group by Two-way ANOVA with Bonferroni's post-hoc test.</p><p>^$$P<0.01</p><p>^$$$P<0.001 diabetic vs. non-diabetic control rats.</p><p>Effects of fluoxetine (FLU) and imipramine (IMIP) on lipid profile and glucose homeostasis in non-diabetic and diabetic rats exposed to chronic restraint stress (CRS).</p

Effects of fluoxetine (FLU) and imipramine (IMIP) on percentage of initial blood glucose level during insulin tolerance test in non-diabetic (A) and diabetic (B) rats exposed to chronic restraint stress (CRS).

<p>Data are mean±SEM; (n = 6).*P<0.05, **P<0.01, ***P<0.001 vs. control group; ^##P<0.01, ^###P<0.001 vs. CRS group by Repeated-measures ANOVA with Bonferroni's post-hoc test. ^$$P<0.01, ^$$$P<0.001 diabetic vs. non-diabetic control rats.</p

Effects of fluoxetine (FLU) versus imipramine (IMIP) on isolated aortic ring phenylephrine (PhE) contractile response (EC_{50 and} Emax) and maximal relaxation response (%) of acetylcholine (Ach) and sodium nitroprusside (SNP) in non-diabetic and diabetic rats exposed to chronic restraint stress (CRS).

<p>Data are mean±SEM (n = 6).</p><p>*P<0.05</p><p>***P<0.001vs control group;</p><p>^###P<0.001 vs. CRS group by Two-way ANOVA with Bonferroni's post-hoc test.</p><p>^$$$P<0.001 diabetic vs. non-diabetic control rats.</p><p>Effects of fluoxetine (FLU) versus imipramine (IMIP) on isolated aortic ring phenylephrine (PhE) contractile response (EC_{50 and} Emax) and maximal relaxation response (%) of acetylcholine (Ach) and sodium nitroprusside (SNP) in non-diabetic and diabetic rats exposed to chronic restraint stress (CRS).</p

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 - Fig 6

<p>(A) Ethidium bromide-stained agarose gel electrophoresis showing the amplified RT-PCR products of TLR-4 (299bp) and β-actin (180 bp) as an internal standard, from aortic homogenates of Wistar rats. First Lane (MW): molecular weight ladder standard. Lane 1: control non-diabetic group. Lane 2: Non-diabetic/CRS vehicle-treated group. Lane 3: Non-diabetic/CRS fluoxetine-treated group. Lane 4: Non-diabetic/CRS imipramine-treated group. Lane 5: Control diabetic group. Lane 6: Diabetic/CRS vehicle-treated group. Lane 7: Diabetic/CRS fluoxetine-treated group. Lane 8: Diabetic/CRS imipramine-treated group. (B) Effects of fluoxetine (FLU) versus imipramine (IMIP) on aortic TLR-4 gene expression (mRNA) as % normalized by β-actin quantity using semi-quantitative RT-PCR in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS). Data are mean±SEM (n = 6). ***P<0.001 vs. control group; ^#P<0.05, ^##P<0.01, ^###P<0.001 vs. CRS group, ^$$$P<0.001 diabetic vs. non-diabetic control rats by Two-way ANOVA with Bonferroni's post-hoc test.</p

Effects of fluoxetine (FLU) versus imipramine (IMIP) on serum corticosterone in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS).

<p>Data are mean±SEM (n = 6). ***P<0.001 vs. control group; ^##P<0.01, ^###P<0.001 vs. CRS group, ^$$$P<0.001 diabetic vs. non-diabetic control rats by Two-way ANOVA with Bonferroni's post-hoc test.</p

TNF-α immunohistochemical staining (IHCX400) of aortic sections in different experimental groups.

<p>(A) Control non-diabetic group with focal faint TNF-a immunostaining (brownish color), (B) Non-diabetic/CRS vehicle-treated group shows moderate diffuse immunostaining, (C) Non-diabetic/CRS fluoxetine-treated and (D) Non-diabetic/CRS imipramine-treated groups show focal mild staining, (E) Control diabetic group (F) Diabetic/CRS vehicle-treated group shows strong diffuse immunostaining, (G) Diabetic/CRS fluoxetine-treated group shows focal mild staining and (H) Diabetic/CRS imipramine-treated group show moderate diffuse immunostaining.</p

Photomicrographs of aortic sections stained by H&E (X640) in different experimental groups.

<p>(A) Control non-diabetic group with unremarkable change, groups (B) Non-diabetic/CRS vehicle-treated group, (C) Non-diabetic/CRS fluoxetine-treated group (D) Non-diabetic/CRS imipramine-treated group, (E) Control diabetic group (F) Diabetic/CRS vehicle-treated group, (G) Diabetic/CRS fluoxetine-treated group, (H) Diabetic/CRS imipramine-treated group. Endothelial lining of tunica intima (↑) and vacuolation of cytoplasm of some smooth muscle fibers (▲).</p

Effects of fluoxetine (FLU) and imipramine (IMIP) on forced swimming (A) and open field (B) tests behavioral changes in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS).

<p>Data are mean±SEM of 9–14 rats/group. ***P<0.001 vs control group, ^##P<0.01, ^###P<0.001 vs. CRS group; ^$P<0.05 diabetic vs. non-diabetic control rats by Two-way ANOVA with Bonferroni's post-hoc test.</p