Regulatory reportAminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-α-induced oxidative stress, colitis and hepatotoxicity in mice
Introduction
Ulcerative colitis (UC) and Crohn's disease (CD) are the two most common chronic relapsing disorders of inflammatory bowel disease (IBD). The chronic bowel inflammation is driven by complex crosstalk between imbalanced immune response [1], [2] and oxidative stress [3], [4], [5], [6], [7]. Among the various gut immune factors, tumor necrosis factor-α (TNF-α) is a key pro-inflammatory cytokine, in IBD [1], [2], [8], [9]. Mucosal levels of TNF-α are elevated in IBD patients [10], [11] and their inhibition [12] or neutralization by anti-TNF-α therapies improved both UC [13] and CD [14]. Moreover, endogenous TNF-α binds to cell surface receptors TNF-R1 (p55) and TNF-R2 (p75) [15] and primes neutrophils, which massively accumulated into inflamed tissues [16]. The molecular mechanism involves the phosphorylation on Ser345-p47phox, the major cytosolic component of the phagocyte NADPH oxidase complex (NOX2) [17]. Primed neutrophils release high amounts of reactive oxygen species (ROS) in synergy with various granular bactericidal peptides and oxidative enzymes, such as myeloperoxidase (MPO), which not only enhance bactericidal efficiency but also drastically, contribute to oxidative stress-induced injuries [16], [17], [18].
Nitric oxide (NO) participates in various physio-pathological events in gastrointestinal tract. Physiological levels of NO released by the constitutive NOsynthase (cNOS) protect the gut mucosa, through the regulation of mucus secretion [18], [19]. However, the large amounts of NO generated by inducible NOsynthase (iNOS) is converted into the highly cytotoxic peroxynitrite, upon reaction with superoxide anion [20], [21], [22], [23]. In addition, the endothelial NOsynthase (eNOS) might be uncoupled by peroxynitrite and converted to a dysfunctional superoxide anion-releasing enzyme, thereby contributing to oxidative stress [24].
Numerous inflammatory diseases including IBD are multifactorial disorders with no therapeutic agents available to simultaneously control both inflammatory immune response and oxidative stress. Aminoguanidine (AG) is a selective inhibitor of iNOsynthase. It reduces the availability of NO by competing with the natural substrate l-arginine [25]. AG also acts as an antioxidant by scavenging ROS [26]. The protective effect of curcumin (Cur), a polyphenolic pigment of turmeric (Curcuma longa L.) on various oxidants-driven diseases is related to its potent ROS scavenging activity [27]. Moreover, Cur can modulate immune response through the inhibition of the key oxidative stress sensitive nuclear transcription factor kappaB (NF-κB) [28], thus resulting in the control of pro-inflammatory enzymes, such as iNOS. Cur also up regulates antioxidant genes expression such as nuclear factor (erythroid-derived 2)-related factor (NRF2) and phase II enzymes of xenobiotic metabolism [29].
Thus, the aim of this study was to evaluate the efficacy of aminoguanidine (AG), as selective iNOS inhibitor and Curcumin (Cur), a naturally occurring antioxidant, on TNF-α-induced oxidative stress, acute colitis and liver toxicity. This oxidative inflammation was assessed macroscopically, on histological and cellular changes and on oxidative stress markers.
Section snippets
Materials
Tumor necrosis factor (TNF-α) was from PeroTech EC (London, GB). Aminoguanidine, curcumin, o-dianisidine hydrochloride, N-(1-napthyl)-ethylenediamine dihydro-chloride, sulphanilamide and thiobarbituric acid were obtained from Sigma Aldrich (St Louis MO, USA). All other chemicals were of analytic grade.
Animals care
Male NMRI mice weighing 20–22 g (Institut Pasteur, Algiers, Algeria), were housed five per cage under controlled conditions throughout the experiments. Standard rodent chow and water were supplied
Dose dependency of TNF-α-induced acute colitis
Mice treated with saline, AG or Cur showed normal colon histology (Fig. 1; Table 3). In contrast, TNF-α induced a dose–dependent increase in colon damage scores. The macroscopic alterations index (1.6 ± 0.24, 2.6 ± 0.24, and 3.2 ± 0.37) reflected in histological lesions (1.2 ± 0.37, 2.2 ± 0.49 and 3.2 ± 0.37) induced by 1, 5 and 10 μg kg− 1 TNF-α challenge, respectively (Table 3, Table 4). Wide hemorrhagic edemas and crypt abscesses massively infiltrated by neutrophils characterized the colons of mice
Discussion
Tumor necrosis factor (TNF)-α is a pro-inflammatory cytokine which plays a crucial role in the pathogenesis of IBD [1], [2], [8], [9]. Moreover, the imbalance between ROS and ROS-neutralizing systems was shown to be a potentiating etiological and/or triggering factor in this disease [3], [4], [5], [6], [7].
This study was conducted in mice, using an immune-mediated model of colitis. Our results showed that TNF-α-induced acute inflammation was reflected in the massive neutrophils influx,
Acknowledgments
The authors declare no conflict of interests. This work was supported by the “Programme National de Recherche en Sciences Fondamentales 2011”, Algiers, Algeria. We are grateful to Dr MC Dang from the “Centre de Recherche Biomédicale Bichat-Beaujon, CRB3”, Paris, France, for her kind gift of TNF-α.
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