Beneficial Effect of Phosphodiesterase-5 Inhibitor in Experimental Inflammatory Bowel Disease; Molecular Evidence for Involvement of Oxidative Stress

Abstract

Inflammatory bowel disease (IBD) is a common and chronic gastrointestinal disorder characterized by intestinal inflammation and mucosal tissue damage. Reactive oxygen metabolites (ROMs) play a pathogenic role in IBD. We aimed to examine the protective effect of sildenafil, a cGMP phosphodiesterase inhibitor, in the experimental mouse model of IBD. Intrarectal instillation of acetic acid was used to induce IBD. Prednisolone was used as the standard drug for comparison. Sildenafil was used at doses of 0.75, 1.5, and 3 mg/kg. Biochemicals and macroscopic and microscopic examinations of colonic tissue were performed. Results indicated that activity of myeloperoxidase (MPO) and lipid peroxidation product (TBARS) markers of oxidative stress are increased in acetic acid-treated groups and are recovered by sildenafil pretreatment and prednisolone. Sildenafil- (1.5 and 3 mg/kg) and prednisolone-treated groups showed significantly lower score values of macroscopic and microscopic characters when compared to the acetic acid-treated group. The beneficial effect of sildenafil (3 mg/kg) was comparable to that of prednisolone. It is concluded that sildenafil is helpful in the management of IBD, which is presumably related to its strong antioxidative stress potential mediated through enhanced cGMP. Results of proper clinical trials will determine the possible efficacy of phosphodiesterase-5 inhibitors in human IBD.

Molecular evidences on the benefit of N-acetylcysteine in experimental colitis

“…It has been suggested that control of oxidative stress in IBD may attenuate biochemical and histopathological variables of IBD [8][9][10][11]. In this regard, existence of oxidative stress in biological fluids such as saliva [12], plasma [13], and colonic mucosal biopsies [2] of subjects with IBD has been already confirmed.…”

“…A long piece of colon (5 cm) was flushed gently with saline, cut open and maintained at -20ºC. To measure biochemical biomarkers, the colonic samples were minced on ice and homogenized in 10 mL of ice cold 50 mM potassium phosphate buffer (pH 6.0), containing 0.5% HETAB and 10 mM EDTA [8][9][10][11]. The homogenates were then sonicated and centrifuged for 20 min at 12000 g and the supernatant was transformed into several microtubes for separate biochemical assays and frozen at -20ºC until analysis.…”

“…Our lab studies have shown reliability of the experimental model of colitis in mouse and rat in terms of both biochemical and pathological changes [8][9][10]11,25].…”

Systemic and metabolic effects of PDE5-inhibitor drugs

“…Since endothelial dysfunction plays a key role in the pathogenesis of the atherosclerotic process, grow ing interest in the effects of PDE5i in preventing atherosclerosis and the vascular endothelium damage has developed [21] . The event that triggers endothelial dysfunction is represented by the reduction of overall antioxidant pool with the consequent reduced response to oxidative stress and the activation of several pro atherogenic processes [22] (Table 3): (1) reduction of NO bioavailability; (2) increased levels of circulating free fatty acids with subsequent subendothelial storage of lipid depots; and (3) increased smooth muscle cell proliferation of the media layer of the vascular wall [23] . Proinflammatory and infective processes may in turn contribute to activate and amplify the acute endothelial injury, thus perpetuating a vicious circle.…”

A Review of the Benefits of Satureja Species on Metabolic Syndrome and Their Possible Mechanisms of Action

“…92 On the other hand, the antiphosphodiesterase activity of flavonoids could raise intracellular cyclic adenosine monophosphate and cyclic guanosine monophosphate levels. 93 The elevation of these levels is involved in reducing oxidative stress, 72,[94][95][96][97][98][99] suppressing secretion of tumor necrosis factora, and inhibiting production of superoxide anions. 100,101 Tumor necrosis factor-a is an adipokine related to inflammation induction and is a key mechanism of disease.…”