Benefit of nicorandil using an immunologic murine model of experimental colitis

Abstract

Inflammatoryboweldisease(IBD)isachronicinflammatoryconditionwithanunknownetiology.Nicorandil,apotassiumchannel opener, has been used for many years for the treatment of angina. Recently, it has been shown that nicorandil possesses some novel traits such as anti-apoptotic, gastroprotective, free radical scavenging, and anti-inflammatory properties. Therefore, we set out to examine the possible beneficial effect of nicorandil in a rat model of IBD. Colitis was induced by rectal administration of 2,4,6-trintrobenzene sulphonic acid (TNBS) into rats. Groups of animals used in this study were sham, control, and exposure to dexamethasone,nicorandil,glibenclamid(apureadenosinetriphosphatesensitivepotassiumchannel(KATP)blocker),ornicorandilplus glibenclamid.Drugswereadministeredbygavageandanimalsweresacrificedafter7days.Biochemicalmarkers,includingTNF-αand IL-1β,ferricreducing/antioxidantpower(FRAP),myeloperoxidase(MPO)activityandthiobarbitoricacid-reactivesubstance(TBARS), weremeasuredinthehomogenateofcolonictissue.Resultsindicatethatnicorandilsignificantlyreducesmacroscopicandhistological damageinducedbyTNBS.NicorandildiminishesMPOactivityandlevelsofTBARS,TNF-α,andIL-1βindamagedcolonictissuewith aconcomitantincreaseinFRAPvalue(P<0.01).Theseeffectswerenotreversedbycoadministrationofglibenclamide.Inconclusion, nicorandilisabletoameliorateexperimentalIBDwithadoseinwhichitdoesnotshowanyanti-hypertensiveeffect,andthemechanism ofwhichispartiallyortotallyindependentfromKATPchannels.Itishypothesizedthatnitricoxidedonationandfree-radicalscavenging propertiesofnicorandilupregulateendothelialnitricoxidesynthasemayberesponsibleforthisphenomenon.Thesefindingssuggest thatnicorandilcanbeusefulintreatmentofIBD,althoughfurtherinvestigationsareneededtoelucidatethemechanismsinvolved.

On the benefits of silymarin in murine colitis by improving balance of destructive cytokines and reduction of toxic stress in the bowel cells

“…An imbalance between proinflammatory and antiinflammatory cytokines is one of the major factors underlying the pathogenesis of IBD. It has been shown that two proinflammatory cytokines, TNF-α and IL-1β are overproduced during the course of inflammation in human IBD [46][47][48] and in TNBS-induced colitis [11]. These key inflammatory cytokines are produced from macrophages, neutrophils and endothelial cells [46].…”

“…In addition to macromolecules oxidation, free radicals and ROS in the inflamed tissue can attract variety of immune cells to the site of inflammation [11]. Polymorphonuclear neutrophils are a group of these cells and their sequestration to the inflamed tissue leads to the overexpression of various inflammatory components, including proinflammatory cytokines (such as IL-1β, IL-6, IL-8 and TNF-α), adhesion molecules, prostaglandins, leukoterienes and platelet-activating factor [50].…”

“…One-hundred µl of each sample was taken for Ferric Reducing Anti-oxidant Power (FRAP) assay and kept at -80ºC until analysis. The remained homogenates were then sonicated and centrifuged for 30 min at 3500 g. The plates were separated and the supernatants were transferred into several microtubes for separate biochemical assays and all were kept at -80ºC until analyses [11].…”

“…Beneficial effects of N-Acetyl cystein have been proved in this condition [10]. Also, nicorandil as a unique potassium channel opener, has been recently shown to be effective in management of IBD in rats [11]. Recently, the effectiveness of many pharmacotherapeutic agents including antibiotics [12][13][14][15], probiotics [16,17] and 5-aminosalicylates [18][19][20] has been meta-analyzed.…”

Nicorandil, Gastrointestinal Adverse Drug Reactions and Ulcerations: A Systematic Review

“…Patel et al [153] argued that nicorandil, in a dose-dependent manner, dephosphorylates myosin and so hinders the actin filament contraction that is necessary for cell migration, as would be required to repair mucosal microtrauma and surgical wounds. Nicorandil has been shown to inhibit endothelial cell mitogenesis and proliferation in experimental settings [154,155] and in animal studies it has shown to hamper the inflammatory pathway, decreasing the production and release of tumor necrosis factor-alpha (TNF-) and other mediators that pave the way for the healing process [156,157].…”