Serotonin and histamine mediate gastroprotective effect of fluoxetine against experimentally-induced ulcers in rats

Abstract

Research in the treatment of gastric ulcer has involved the investigation of new alternatives, such as anti-depressant drugs. The present study was designed to investigate the gastroprotective effects of fluoxetine against indomethacin and alcohol induced gastric ulcers in rats and the potential mechanisms of that effect. Fluoxetine (20 mg/kg) was administered IP for 14 days. For comparative purposes, other rats were treated with ranitidine (30 mg/kg). Thereafter, after 24 h of fasting, INDO (100 mg/kg) or absolute alcohol (5 ml/kg) was administered to all rats (saline was administered to naïve controls) and rats in each group were sacrificed 5 h (for INDO rats) or 1 h (for alcohol rats) later. Macroscopic examination revealed that both fluoxetine and ranitidine decreased ulcer scores in variable ratios, which was supported by microscopic histopathological examination. Biochemical analysis of fluoxetine-or ranitidine-pre-treated host tissues demonstrated reductions in tumor necrosis factor (TNF)-and myeloperoxidase (MPO) levels and concomitant increases in gastric pH, nitric oxide (NO) and reduced glutathione (GSH) contents. Fluoxetine, more than ranitidine, also resulted in serotonin and histamine levels nearest to control values. Moreover, immuno-histochemical analysis showed that fluoxetine markedly enhanced expression of cyclooxygenases COX-1 and COX-2 in both models; in comparison, ranitidine did not affect COX-1 expression in either ulcer model but caused moderate increases in COX-2 expression in INDOinduced hosts and high expression in alcohol-induced hosts. The results here indicated fluoxetine exhibited better gastroprotective effects than ranitidine and this could be due to anti-secretory, anti-oxidant, anti-inflammatory and anti-histaminic effects of the drug, as well as a stabilization of gastric serotonin levels. ARTICLE HISTORY

Fluoxetine‐induced hepatic lipid accumulation is mediated by prostaglandin endoperoxide synthase 1 and is linked to elevated 15‐deoxy‐Δ12,14PGJ2

“…In this study, we have shown that fluoxetine induced hepatic lipid accumulation in association with upregulated mRNA expression of Ptgs1 and Ptgs2 . These results are consistent with a previous study which reported that fluoxetine markedly enhanced the expression of PTGS1 and PTGS2 in gastric tissue (Salem Sokar et al, 2016). PTGS1 and PTGS2 are involved in the conversion of arachidonic acid to Prostaglandin H2 (PGH 2 ), an important precursor of other downstream prostaglandins (Nagao et al, 2013).…”

“…For example, the SSRI vortioxetine has been shown to inhibit the activity of both PTGS1 and PTGS2, while fluvoxamine significantly decreased the expression of PTGS2 (Marčec & Likić, 2021; Naji Esfahani et al, 2019; Talmon et al, 2020). Notably, The SSRI fluoxetine has been shown to increase the protein expression of PTGS1 and PTGS2, elevate the cerebrospinal fluid concentration of 15d‐PGJ 2 , and increase secretion of 15d‐PGJ 2 from raphe serotonergic neurons (Launay et al, 2011; Salem Sokar et al, 2016; Simplicio et al, 2015). Therefore, the goal of this study was to test the hypothesis that increases in hepatic prostaglandin production underlie increased fluoxetine‐induced lipid accumulation in vitro.…”

“…Notably, The SSRI fluoxetine has been shown to increase the protein expression of PTGS1 and PTGS2, elevate the cerebrospinal fluid concentration of 15d-PGJ 2 , and increase secretion of 15d-PGJ 2 from raphe serotonergic neurons (Launay et al, 2011;Salem Sokar et al, 2016;Simplicio et al, 2015). Therefore, the goal of this study was to test the hypothesis that increases in hepatic prostaglandin production underlie increased fluoxetine-induced lipid accumulation in vitro.…”

Alanyl‐glutamine Heals Indomethacin‐induced Gastric Ulceration in Rats Via Antisecretory and Anti‐apoptotic Mechanisms

“…Animals (n = 10 rats/group) were randomly allocated into 5 groups; viz, the control group, where rats received the vehicle (1% Tween 80), whereas those in the other groups received indomethacin (100 mg/kg; p.o. ; Sigma‐Aldrich, MO) suspended in the vehicle (20). Gastropathic animals were further subdivided into the indomethacin untreated group and those treated 4 hours after indomethacin with pantoprazole (30 mg/kg, i.p.…”

Dose of selective serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding in older adults

“…Fluoxetine was found to stimulate gastric acid secretion in a dose–response fashion, and larger amounts of gastric acid could cause the formation of chronic ulcers (Brzozowski et al, 2000; Salam, 2004). However, fluoxetine decreased the incidence of indomethacin (one kind of NSAID)-induced ulcers and ulcer bleeding in rats (Ji et al, 2012; Salem Sokar et al, 2016). In our analysis, the dose–response relationship between fluoxetine and UGIB remained significant after controlling for NSAID use and other potential confounders.…”