Effects of trimetazidine in ethanol‐ and acetic acid‐induced colitis: oxidant/anti‐oxidant status

Abstract

There is overwhelming evidence in favour of a significant role of reactive oxygen metabolites (ROM) in the pathophysiology of inflammatory bowel disease (IBD) in man and in experimental animal models. This study was undertaken to investigate the possible protective effects of pretreatment with trimetazidine (TMZ) on the oxidant-anti-oxidant balance in ethanol- and acetic acid-induced colonic damage in rats. TMZ was chosen because of its various cytoprotective features (preserving cellular ATP levels, limiting intracellular acidosis and limiting inorganic phosphate, Na(+) and Ca(2+) accumulation) and anti-oxy characteristics which were previously reported. A total of 80 rats were randomized into eight major groups each consisting of 10 animals. Animals in groups 1, 2 and 3 served as models of ethanol-induced colitis (0.25 ml of 30% (v/v) ethanol), while group 4 served as their control. Animals in groups 5, 6 and 7 served as models of acetic acid-induced colitis (1 ml of 4% (v/v) acetic acid), while group 8 served as their control. TMZ was administered 5 mg/kg by intrarectal (i.r.) and intraperitoneal (i.p.) routes to groups 1, 2, 5 and 6. Intraperitoneal administration of TMZ was used in order to evaluate its systemic effect while i.r. administration was used to determine its local effect. After decapitation, colon mucosa samples were obtained and evaluated macroscopically and microscopically. Myeloperoxidase (MPO) activities as markers for inflammation, malondialdehyde (MDA) levels as markers for oxidant stress and reduced glutathione (GSH) and oxidized glutathione (GSSG) levels as markers for anti-oxidant status were determined. Acute colitis was observed in macroscopic and microscopic evaluation in ethanol- and acetic acid-administered groups compared with controls (P = 0.000). The macroscopic and microscopic scores in colitis groups were correlated with MPO activities (r = 0.5365, P = 0.000 and r = 0.5499, P = 0.000, respectively). MDA and GSSG levels in the acetic acid-induced colitis group were higher compared with ethanol-induced colitis group (P < 0.008 and P < 0.005, respectively), while GSH levels were significantly lower (P < 0.05). While TMZ pretreatment did not improve the oxidant state, it preserved the GSH levels significantly (P < 0.05). In conclusion, ethanol- and acetic acid-induced colitis models are appropriate experimental colitis models which in many ways manifest the characteristics seen in tissue injury related to colitis in humans. Of these two, the acetic acid-induced colitis model proved more suitable than the ethanol model for investigating the alterations in long-term and in more severe tissue injury. While TMZ pretreatment via i.p. or i.r. route did not improve the oxidative-inflammative state in either of these models, it did contribute significantly to the preservation of the anti-oxidant pool via the conservation of intracellular GSH levels. This conserving effect of TMZ was substantially more pronounced in the i.p. route compared with the i.r. route. Based on our results, we concl...

Trimetazidine reduces the degree of fibrosis in alkali burns of the esophagus

“…As a result, TMZ has improved the histopathologic damage and in addition decreased tissue hydroxyproline content. In previous studies, the protective effect of TMZ has been demonstrated in various experimental damage models of the gastrointestinal system in rats [22,23]. Girgin et al [22] have shown that TMZ contributed significantly to the preservation of the antioxidant pool via conservation of intracellular glutathione levels.…”

“…In previous studies, the protective effect of TMZ has been demonstrated in various experimental damage models of the gastrointestinal system in rats [22,23]. Girgin et al [22] have shown that TMZ contributed significantly to the preservation of the antioxidant pool via conservation of intracellular glutathione levels. Trimetazidine protected the histological appearance of the pancreas and considerably reduced malondialdehyde concentration in acute pancreatitis model in rats, indicating that the beneficial effect was achieved by the elimination of free oxygen radicals [23].…”

Mitochondrial dysfunction in inflammatory bowel disease

“…Additionally, the infiltration of leukocytes, monocytes, and neutrophils during inflammation can further enhance intestinal ROS production through both respiratory burst enzymes and prostaglandin and leukotriene metabolism (Babbs, 1992 ). Several studies have demonstrated increased ROS/RNS levels within the intestinal epithelium of patients with IBD (Kruidenier and Verspaget, 2002 ; Pravda, 2005 ; Rezaie et al, 2007 ) and in murine models of experimental colitis (Girgin et al, 1999 ; Tham et al, 2002 ; Narushima et al, 2003 ; Sundaram et al, 2003 ; Oz et al, 2005 ; Siddiqui et al, 2006 ; dos Reis et al, 2009 ; Kajiya et al, 2009 ; Abdolghaffari et al, 2010 ; Yao et al, 2010 ; Lenoir et al, 2011 ; Ock et al, 2011 ; Sengül et al, 2011 ; Borrelli et al, 2013 ; Arab et al, 2014 ). High concentrations of oxidized molecules have also been measured in the plasma, serum, exhaled air, and saliva of patients with IBD (Tüzün et al, 2002 ; Rezaie et al, 2006 ).…”

Trimetazidine, a metabolic modulator, attenuates silica‐induced pulmonary fibrosis and decreases lactate levels and LDH activity in rats

“…Rats were initially weighed and randomized into three groups ( n = 10); control, silica and silica‐TMZ in which silica or saline were intranasally instilled on Day 1, and oral treatments with either TMZ (7 mg/kg/day, [ 26,27 ] silica‐TMZ group) or the vehicle for TMZ (0.5% CMC, 10 ml/kg/day, both control group and silica group) were administered orally for 60 days. Of note, shorter‐term studies (7 days) were used to test the beneficial effects on the inflammatory rather than the fibrotic phase that follows exposure to silica.…”