Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha.

Santucci, Luca; Fiorucci, Stefano; Giansanti, Michele; P, Brunori; Matteo, Francesco Maria Di; Morelli, Antonio

doi:10.1136/gut.35.7.909

Cited by 192 publications

(125 citation statements)

References 25 publications

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“…Although their efficiency in most cases, NSAIDs were proven to induce the secretion of TNF-a especially when they are used chronically. Overproduction of TNF-a believes to play a key role in the onset and progression of various pathologies such as disseminated intravascular coagulation and death in septic choc and cerebral malaria (Medana et al 1997;Murphy et al 1998) and a range of inflammatory diseases including asthma (Bj€ ornsdottir & Cypcar 1999), dermatitis, inflammatory bowel disease, cystic fibrosis, rheumatoid arthritis and multiples sclerosis (Sekut & Connolly 1996); in addition, TNF-a has been shown to be a crucial mediator of NSAIDs-induced gastric mucosal injury (Santucci et al 1994). In spite of enormous efforts, the only available drugs to inhibit TNFa activity, in clinics, are proteins (Etanercept, Infliximab, Adalimumab and Anakinra) that display adverse effects such as aplastic anaemia, pancytopenia, vasculitis, demyelination and congestive heart failure (Desai & Furst 2006).…”

Section: Introductionmentioning

confidence: 99%

In vitroimmunomodulatory activity andin vivoanti-inflammatory and analgesic potential with gastroprotective effect of the Mediterranean red algaLaurencia obtusa

Lajili

Deghrigue

Amor

et al. 2016

Pharmaceutical Biology

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Context: Red algae have been recognized as a rich natural source of compounds possessing interesting biological and pharmacological activities. Objective: This work investigates anti-inflammatory, analgesic and gastroprotective activities of MeOH/ CH 2 Cl 2 crude extract and its fractions F1 (50% MeOH) and F2 (80% MeOH) from the whole alga plant Laurencia obtusa Hudson (Rhodomelaceae). Materials and methods: Anti-inflammatory activity was evaluated in vitro using cytometric bead array (CBA) technology to follow up the secretion of tumour necrosis factor alpha (TNF-a) in lipopolysaccharide activated THP-1 monocytic cells at doses of 10-250 lg/mL and in vivo using carrageenan-induced paw oedema in Wistar rats at doses of 25, 50, 100 and 200 mg/kg. Crude extract and fractions were tested at the doses of 25, 50, 100 and 200 mg/kg for peripheral and central analgesic activity by acetic acid-induced writhing test and hot-plate method, respectively, in Swiss albino mice. Gastroprotective activity was evaluated using HCl/ethanol-induced gastric ulcer test in rats at doses of 25, 50, 100 and 200 mg/kg. Results: Crude extract, F1 and F2 showed an interesting inhibition of TNF-a secretion with IC 50 values of 25, 52 and 24 lg/mL, respectively, and a significant anti-inflammatory activity in vivo (p < 0.01), 3 h after carrageenan injection, the oedema inhibition was 55.37%, 52.18% and 62.86%, respectively, at the dose of 100 mg/kg. Furthermore, they showed a significant peripheral analgesic activity with 53.79%, 55.92% and 57.37% (p < 0.01) of writhing inhibition, respectively. However, no significant activity was found in the hotplate test. An interesting gastroprotective effect was observed with crude extract and its fractions F1 and F2 with a gastric ulcer inhibition of 65.48%, 77.42% and 81.29%, respectively, at the dose of 50 mg/kg. Discussion and conclusion: These results suggest that L. obtusa might be used as a potential source of natural anti-inflammatory and analgesic agents with gastroprotective effect. ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 99%

In vitroimmunomodulatory activity andin vivoanti-inflammatory and analgesic potential with gastroprotective effect of the Mediterranean red algaLaurencia obtusa

Lajili

Deghrigue

Amor

et al. 2016

Pharmaceutical Biology

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“…4,5 Previous reports have studied a range of doses of pentoxifylline with signi®cant effects occurring with 100 mg/kg and higher concentrations up to 200 mg/kg. 8 Following treatment with pentoxifylline (200 mg/kg) rats showed signs of toxicity including lethargy and hypersalivation, thus for our study where treatment with pentoxifylline was of a more chronic nature we chose a dose of 100 mg/kg which caused no signs of toxicity. In preliminary studies animals were sacri®ced at 24 h following TNBS to verify the presence of ulcers and in¯ammation.…”

Section: Methodsmentioning

confidence: 99%

Effect of acute pentoxifylline treatment in an experimental model of colitis

Peterson

Davey

1997

Aliment Pharmacol Ther

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INTRODUCTIONIn the present study the animal model of in¯ammatory bowel disease is caused by the agent trinitrobenzene sulphonic acid (TNBS). This was ®rst used in 1989 by Morris et al., and is based on the hypothesis of Ward Shorter et al. which presumes that an increase in mucosal permeability in Crohn's disease results in entry into the lamina propria of a luminal antigen that is not adequately cleared by the mucosal immune system. 1±3 Instillation of a solution containing ethanol and TNBS into the distal colon of the rat elicits an immune response. The ethanol acts as a barrier breaker while TNBS acts as the hapten with resulting development of severe transmural granulomatous in¯ammation similar to that seen in in¯ammatory bowel disease. In this animal model we assess the effects of pentoxifylline, a methylxanthine which has been reported to reduce in¯ammation in other animal models and to block ®brosis in animal models of hepatic ®brosis. 4,5 Because of the association of in¯ammatory bowel disease with stricture formation, and the increased collagen deposition in SUMMARY Background: The effect of acute pentoxifylline treatment in an experimental model of colitis was assessed using the trinitrobenzene sulphonic acid (TNBS)-induced rat model of colitis. Methods: Animals were treated with intracolonic injection (250 lL) of TNBS (50 mg in 50% ethanol) to induce in¯ammation and ulcers. Animals received pentoxi®lline (100 mg/kg intracolonically) or saline 24 and 48 h following TNBS treatment. Five days following TNBS treatment, colons were dissected and scored according to the morphology damage score. The colons were then rolled longitudinally, ®xed in formalin and embedded in paraf®n. The collagen content of colonic sections was determined by a Sirius red±Fast green technique. Results: Animals treated with TNBS alone had signi®cantly higher gross morphology damage scores

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“…Myeloperoxidase released into the supernatant (250 lL) was assayed spectrophotometrically using TMB as substrate. 25 The sample was both incubated and assayed in triplicate. Myeloperoxidase secreted during incubation was expressed as a percentage of total myeloperoxidase present in PMN at the beginning of the incubation minus the enzyme secreted prior to starting incubation.…”

Section: Myeloperoxidase Releasementioning

confidence: 99%

NSAIDs upregulate β₂‐integrin expression on human neutrophils through a calcium‐dependent pathway

Fiorucci

Santucci

Gerli

et al. 1997

Aliment Pharmacol Ther

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Background: Margination of circulating neutrophils (PMN) into the gastric microcirculation is an early and critical event in the pathogenesis of non‐steroidal antinflammatory drug (NSAID)‐induced gastropathy. This effect is mediated through the upregulation of β2 integrins on the PMN surface. Aims: To investigate whether indomethacin modulates: (1) Mac‐1 expression; (2) Ca2+ mobilization ([Ca2+]i), protein kinase C and nitric oxide accumulation; and (3) mitogen‐associated protein kinase phosphorylation in human PMN. Methods: Human PMN were isolated by centrifugation through a double Ficoll gradient. [Ca2+]i was measured in PMN loaded with fura‐2 and Mac‐1 expression by flow cytometry. Results: Indomethacin caused a concentration‐ and time‐dependent upregulation of CD11b and CD18 expression and PMN adhesion to endothelial cells. Maximal upregulation of Mac‐1 expression (40–50%) occurred after a 30‐min incubation with 0.1 mM indomethacin. The effect was prevented by removing the Ca2+. Ionomycin and thapsigargin caused a 7–10‐fold increase in [Ca2+]i and a 2–4‐fold increase in Mac‐1 expression. Indomethacin induced a concentration‐dependent phosphorylation of a 41‐kDa mitogen‐associated protein kinase. Tyrosine kinase inhibitors prevented the effect of indomethacin on Mac‐1 expression and Ca2+ mobilization. Indomethacin and ionomycin increased superoxide generation, myeloperoxidase secretion and PMN adherence to endothelial cells and stimulated nitric oxide production. Indomethacin‐induced Mac‐1 upregulation was prevented by a nitric oxide synthase inhibitor. Conclusions: Indomethacin‐induced upregulation of Mac‐1 is mediated by changes in [Ca2+]i and nitric oxide. Phosphorylation of the 41‐kDa mitogen‐associated protein isoform is a previously unreported target of NSAID action. These effects might help to explain the ability of indomethacin to cause gastric neutrophil margination.

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Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha.

Cited by 192 publications

References 25 publications

In vitroimmunomodulatory activity andin vivoanti-inflammatory and analgesic potential with gastroprotective effect of the Mediterranean red algaLaurencia obtusa

In vitroimmunomodulatory activity andin vivoanti-inflammatory and analgesic potential with gastroprotective effect of the Mediterranean red algaLaurencia obtusa

Effect of acute pentoxifylline treatment in an experimental model of colitis

NSAIDs upregulate β₂‐integrin expression on human neutrophils through a calcium‐dependent pathway

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Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: role of tumour necrosis factor alpha.

Cited by 192 publications

References 25 publications

In vitroimmunomodulatory activity andin vivoanti-inflammatory and analgesic potential with gastroprotective effect of the Mediterranean red algaLaurencia obtusa

In vitroimmunomodulatory activity andin vivoanti-inflammatory and analgesic potential with gastroprotective effect of the Mediterranean red algaLaurencia obtusa

Effect of acute pentoxifylline treatment in an experimental model of colitis

NSAIDs upregulate β2‐integrin expression on human neutrophils through a calcium‐dependent pathway

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Product

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NSAIDs upregulate β₂‐integrin expression on human neutrophils through a calcium‐dependent pathway