Therapeutic implications of antioxidant defense in acute pancreatitis
Zhao-Xiang Bian and Siu-Wai Tsang
Hong Kong, China
Author Affiliations: Clinical Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China (Bian ZX and Tsang SW)
Corresponding Author: Prof. Zhao-Xiang Bian, MD, PhD, Director of Clinical Division, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, China (Tel: +852-34112905; Fax: +852-34112929; Email:
© 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.
doi: 10.1016/S1499-3872(14)60266-6
Published online June 23, 2014.
Contributors: BZX and TSW wrote the manuscript. BZX is the guarantor.
Funding: None.
Ethical approval: Not needed.
Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
Acute pancreatitis is an inflammation initially localized in the pancreas, which may be accompanied with severe complications such as multi-organ failure, gastrointestinal hemorrhage and malnutrition. One in ten severe cases of acute pancreatitis develops systemic inflammatory response syndrome. Despite treatment, acute pancreatitis can be a life-threatening disease as its mortality rate amounts to 5%-10% in general, and up to 35% in cases of severe course.[1] Over the years, the role of oxidative stress has been highlighted in the pathophysiology of acute pancreatitis. The level of intensification of oxidative stress correlates to the severity of the disease, the risk of systemic complications and prognosis.[2, 3] To this end, the generation of reactive oxygen species (ROS) has been implicated in this debilitating inflammation as well as the parenchymal damages of the gland and surrounding tissues or distant organs.[4, 5] In fact, ROS, products of mitochondrial metabolism, are plausibly arisen from several major antioxidant defensive mechanisms including protein oxidation, lipid peroxidation and glutathione depletion. Under normal condition, these toxic intermediates are immediately neutralized by the natural non-enzymatic scavengers, including glutathione and vitamins C and E, and antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx).[6, 7] When the ability of detoxification is impaired under pancreatitis condition, oxidative stress is resulted from the over-production of ROS and their accumulation in the tissues. The enhancement of antioxidant defense in acute pancreatitis can be achieved through direct scavenging of toxic ROS and/or preservation of the activity of antioxidant enzymes,[2-7] and is of great therapeutic potentials.
In the current study,[8] acute pancreatitis was induced by cerulein administration, which is the most widely used approach complementing with a highly reproducible course for the study of pancreatitis in rodents.[9] Evaluation of different markers of oxidative stress and antioxidant status in the course of acute pancreatitis is extremely important for evaluating the effectiveness of antioxidant therapeutic approaches. Authors clearly demonstrated the cerulein-induced pancreatic damages in terms of protein oxidation and lipid peroxidation. As conducted with established methods, effects of melatonin were observed in the marked suppression of 2, 4-dinitrophenylhydrazine-reactive protein carbonyls and malondialdehyde-dependent chromophores.[10, 11] Though the pancreatic levels of reduced glutathione were not measured, the preservation of cellular GPx activities by melatonin was indicative to its antioxidant role in glutathione depletion under pancreatitis condition. The authors also examined the total antioxidant status, which was presented as Trolox activities, in pancreatic samples of the experimental animals. The upregulation of intracellular scavenging activity of Trolox indeed strengthened the antioxidative role of melatonin in acute pancreatitis.[12] Further investigation on oxidative stress-related mechanisms may involve xanthine oxidase, cytochromes P450, NADPH oxidases, SOD, catalase and nitric oxide synthase as they are believed to be the potential sources of ROS.
Melatonin, a derivative of L-tryptophan, is well recognized as a pineal hormone; however, accumulating evidence has demonstrated that it serves as a scavenger of ROS as well as an activator of antioxidant enzymes. Ma and colleagues[13] reported that this highly lipophilic hormone protected mice from hepatic and renal tissue injury via diminishing the production of pro-inflammatory cytokines and the accumulation of ROS. Likewise, from the study of Dehghan et al,[14] brain edema was notably decreased in melatonin-treated rats with traumatic brain injury, in which substantial activation of SOD and GPx was observed. Carrasco and colleagues[8] proposed that ROS and pro-inflammatory mediators trigger common signal transduction pathways such as nuclear factor-kappa B and nuclear factor erythroid 2-related factor 2, for robust amplification of inflammatory cascades as well as activation of antioxidant enzymes. Hence, the antioxidant effects of melatonin could be related to the inhibition of the inflammatory signaling pathways for its directly neutralizing of toxic products and indirectly improving the total oxidative status. Further, owing to its small molecular size and amphipathic property, melatonin can penetrate exceptionally well into subcellular compartments. In consequence, melatonin could stabilize biological membranes, specifically in the maintenance of membrane fluidity, in counteracting the free radicals generated in inflammatory diseases, tissue injuries and aging events.[15]
According to a recent report,[16] the severity of acute pancreatitis was significantly ameliorated in rats pretreated with L-tryptophan at a dose as low as 50 mg/kg when inflammatory processes were remarkably attenuated, but the activities of antioxidant enzymes were enhanced. The ameliorative effects of L-tryptophan were probably dependent on its conversion to melatonin as plasma melatonin levels were raised up by approximately 5 folds after L-tryptophan administration.[16] Thus, endogenous melatonin protected the pancreas effectively from inflammatory damages. As the pool of indoleamine in mammals depends on its synthesis in the pineal gland to a great degree, the role of pineal melatonin in pancreatic protection becomes questionable. A piece of supporting evidence from Cöl and colleagues that the application of melatonin in pinealectomized rats during the course of acute pancreatitis could significantly reduce oxidative damages in pancreatic parenchyma.[17] Taken together, the beneficial effects of melatonin shown in previous and current findings suggest that melatonin is worthy to be employed in preclinical and clinical studies as a therapeutic agent or an adjuvant therapy for the treatment of acute and chronic pancreatitis.
1 Lund H, Tønnesen H, Tønnesen MH, Olsen O. Long-term recurrence and death rates after acute pancreatitis. Scand J Gastroenterol 2006;41:234-238. PMID: 16484129
2 Leung PS, Chan YC. Role of oxidative stress in pancreatic inflammation. Antioxid Redox Signal 2009;11:135-165. PMID: 18837654
3 Booth DM, Murphy JA, Mukherjee R, Awais M, Neoptolemos JP, Gerasimenko OV, et al. Reactive oxygen species induced by bile acid induce apoptosis and protect against necrosis in pancreatic acinar cells. Gastroenterology 2011;140:2116-2125. PMID: 21354148
4 Braganza JM. Towards a novel treatment strategy for acute pancreatitis. 2. Principles and potential practice. Digestion 2001;63:143-162. PMID: 11351142
5 Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet 2008;371:143-152. PMID: 18191686
6 Bergamini CM, Gambetti S, Dondi A, Cervellati C. Oxygen, reactive oxygen species and tissue damage. Curr Pharm Des 2004;10:1611-1626. PMID: 15134560
7 Galecka E, Mrowicka M, Malinowska K, Galecki P. Role of free radicals in the physiological processes. Pol Merkur Lekarski 2008;24:446-448. PMID: 18634393
8 Carrasco C, Rodríguez AB, Pariente JA. Effects of melatonin on the oxidative damage and pancreatic antioxidant defenses in cerulein-induced acute pancreatitis in rats. Hepatobiliary Pancreat Dis Int 2014;13:442-446.
9 Dabrowski A, Konturek SJ, Konturek JW, Gabryelewicz A. Role of oxidative stress in the pathogenesis of caerulein-induced acute pancreatitis. Eur J Pharmacol 1999;377:1-11. PMID: 10448919
10 Ip SP, Tsang SW, Wong TP, Che CT, Leung PS. Saralasin, a nonspecific angiotensin II receptor antagonist, attenuates oxidative stress and tissue injury in cerulein-induced acute pancreatitis. Pancreas 2003;26:224-229. PMID: 12657946
11 Tsang SW, Ip SP, Leung PS. Prophylactic and therapeutic treatments with AT 1 and AT 2 receptor antagonists and their effects on changes in the severity of pancreatitis. Int J Biochem Cell Biol 2004;36:330-339. PMID: 14643897
12 Distelmaier F, Visch HJ, Smeitink JA, Mayatepek E, Koopman WJ, Willems PH. The antioxidant Trolox restores mitochondrial membrane potential and Ca2+-stimulated ATP production in human complex I deficiency. J Mol Med (Berl) 2009;87:515-522. PMID: 19255735
13 Ma P, Yan B, Zeng Q, Liu X, Wu Y, Jiao M, et al. Oral exposure of Kunming mice to diisononyl phthalate induces hepatic and renal tissue injury through the accumulation of ROS. Protective effect of melatonin. Food Chem Toxicol 2014;68:247-256. PMID: 24685826
14 Dehghan F, Khaksari Hadad M, Asadikram G, Najafipour H, Shahrokhi N. Effect of melatonin on intracranial pressure and brain edema following traumatic brain injury: role of oxidative stresses. Arch Med Res 2013;44:251-258. PMID: 23608674
15 García JJ, López-Pingarrón L, Almeida-Souza P, Tres A, Escudero P, García-Gil FA, et al. Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: a review. J Pineal Res 2014;56:225-237. PMID: 24571249
16 Jaworek J, Leja-Szpak A, Bonior J, Nawrot K, Tomaszewska R, Stachura J, et al. Protective effect of melatonin and its precursor L-tryptophan on acute pancreatitis induced by caerulein overstimulation or ischemia/reperfusion. J Pineal Res 2003;34:40-52. PMID: 12485371
17 Cöl C, Dinler K, Hasdemir O, Büyüka?ik O, Bu?dayci G, Terzi H. Exogenous melatonin treatment reduces hepatocyte damage in rats with experimental acute pancreatitis. J Hepatobiliary Pancreat Sci 2010;17:682-687. PMID: 20464559
Received April 21, 2014
Accepted after revision May 6, 2014