Introduction and Aim Mangafodipir is a contrast agent used in magnetic resonance imaging that concentrates in the liver and displays pleiotropic antioxidant properties. Since reactive oxygen species are involved in ischemia-reperfusion damages, we hypothesized that the use of mangafodipir could prevent liver lesions in a mouse model of hepatic ischemia reperfusion injury. Mangafodipir (MnDPDP) was compared to ischemic preconditioning and intermittent inflow occlusion for the prevention of hepatic ischemia-reperfusion injury in the mouse. Methods Mice were subjected to 70% hepatic ischemia (continuous ischemia) for 90 min. Thirty minutes before the ischemic period, either mangafodipir (10 mg/kg) or saline was injected intraperitoneally. Those experimental groups were compared with one group of mice preconditioned by 10 minutes' ischemia followed by 15 minutes' reperfusion, and one group with intermittent inflow occlusion. Hepatic ischemia-reperfusion injury was evaluated by measurement of serum levels of aspartate aminotransferase (ASAT) activity, histologic analysis of the livers, and determination of hepatocyte apoptosis (cytochrome c release, caspase 3 activity). The effect of mangafodipir on the survival rate of mice was studied in a model of total hepatic ischemia. Results Mangafodipir prevented experimental hepatic ischemia-reperfusion injuries in the mouse as indicated by a reduction in serum ASAT activity (P<0.01), in liver tissue damages, in markers of apoptosis (P<0.01), and by higher rates of survival in treated than in untreated animals (P<0.001). The level of protection by mangafodipir was similar to that observed following intermittent inflow occlusion and higher than after ischemic preconditioning. Conclusions Mangafodipir is a potential new preventive treatment for hepatic ischemia-reperfusion injury.
References
[1]
Gozzetti G, Mazziotti A, Grazi GL, Jovine E, Gallucci A, et al. (1995) Liver resection without blood transfusion. Br J Surg 82: 1105–1110.
[2]
Matsumata T, Ikeda Y, Hayashi H, Kamakura T, Taketomi A, et al. (1993) The association between transfusion and cancer-free survival after curative resection for hepatocellular carcinoma. Cancer 72: 1866–1871.
[3]
Man K, Fan ST, Ng IO, Lo CM, Liu CL, et al. (1997) Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg 226: 704–711; discussion 711–703.
[4]
Nagasue N, Uchida M, Kubota H, Hayashi T, Kohno H, et al. (1995) Cirrhotic livers can tolerate 30 minutes ischaemia at normal environmental temperature. Eur J Surg 161: 181–186.
[5]
Makuuchi M, Mori T, Gunven P, Yamazaki S, Hasegawa H (1987) Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet 164: 155–158.
[6]
Ezaki T, Seo Y, Tomoda H, Furusawa M, Kanematsu T, et al. (1992) Partial hepatic resection under intermittent hepatic inflow occlusion in patients with chronic liver disease. Br J Surg 79: 224–226.
[7]
Peralta C, Hotter G, Closa D, Gelpi E, Bulbena O, et al. (1997) Protective effect of preconditioning on the injury associated to hepatic ischemia-reperfusion in the rat: role of nitric oxide and adenosine. Hepatology 25: 934–937.
[8]
Belghiti J, Noun R, Malafosse R, Jagot P, Sauvanet A, et al. (1999) Continuous versus intermittent portal triad clamping for liver resection: a controlled study. Ann Surg 229: 369–375.
[9]
Clavien PA, Selzner M, Rudiger HA, Graf R, Kadry Z, et al. (2003) A prospective randomized study in 100 consecutive patients undergoing major liver resection with versus without ischemic preconditioning. Ann Surg 238: 843–850; discussion 851–842.
[10]
Peralta C, Bulbena O, Xaus C, Prats N, Cutrin JC, et al. (2002) Ischemic preconditioning: a defense mechanism against the reactive oxygen species generated after hepatic ischemia reperfusion. Transplantation 73: 1203–1211.
[11]
Tejima K, Arai M, Ikeda H, Tomiya T, Yanase M, et al. (2004) Ischemic preconditioning protects hepatocytes via reactive oxygen species derived from Kupffer cells in rats. Gastroenterology 127: 1488–1496.
[12]
Hassan-Khabbar S, Vamy M, Cottart CH, Wendum D, Vibert F, et al. (2010) Protective effect of post-ischemic treatment with trans-resveratrol on cytokine production and neutrophil recruitment by rat liver. Biochimie 92: 405–410.
[13]
Nieuwenhuijs VB, De Bruijn MT, Padbury RT, Barritt GJ (2006) Hepatic ischemia-reperfusion injury: roles of Ca2+ and other intracellular mediators of impaired bile flow and hepatocyte damage. Dig Dis Sci 51: 1087–1102.
[14]
Jaeschke H (1991) Reactive oxygen and ischemia/reperfusion injury of the liver. Chem Biol Interact 79: 115–136.
[15]
McCord JM (1985) Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 312: 159–163.
[16]
Sasaki H, Matsuno T, Nakagawa K, Matsuoka J, Tanaka N (1998) Superoxide induces hepatocyte apoptosis during the early phase of reperfusion after murine liver ischemia. Transplant Proc 30: 2958–2959.
[17]
Stein HJ, Oosthuizen MM, Hinder RA, Lamprechts H (1991) Oxygen free radicals and glutathione in hepatic ischemia/reperfusion injury. J Surg Res 50: 398–402.
[18]
Yabe Y, Kobayashi N, Nishihashi T, Takahashi R, Nishikawa M, et al. (2001) Prevention of neutrophil-mediated hepatic ischemia/reperfusion injury by superoxide dismutase and catalase derivatives. J Pharmacol Exp Ther 298: 894–899.
[19]
Nguyen WD, Kim DH, Alam HB, Provido HS, Kirkpatrick JR (1999) Polyethylene glycol-superoxide dismutase inhibits lipid peroxidation in hepatic ischemia/reperfusion injury. Crit Care 3: 127–130.
[20]
Hirakawa A, Takeyama N, Nakatani T, Tanaka T (2003) Mitochondrial permeability transition and cytochrome c release in ischemia-reperfusion injury of the rat liver. J Surg Res 111: 240–247.
Schauer RJ, Gerbes AL, Vonier D, Meissner H, Michl P, et al. (2004) Glutathione protects the rat liver against reperfusion injury after prolonged warm ischemia. Ann Surg 239: 220–231.
[23]
Elizondo G, Fretz CJ, Stark DD, Rocklage SM, Quay SC, et al. (1991) Preclinical evaluation of MnDPDP: new paramagnetic hepatobiliary contrast agent for MR imaging. Radiology 178: 73–78.
[24]
Ali BH, Bashir AA (1993) Comparative modulating effects of captopril, diltiazem, dietary calcium and pyridoxal-5′-phosphate on gentamicin-induced nephrotoxicity in the rat. Gen Pharmacol 24: 1279–1283.
[25]
Calabrese V, Calderone A, Ragusa N, Rizza V (1996) Effects of Metadoxine on cellular status of glutathione and of enzymatic defence system following acute ethanol intoxication in rats. Drugs Exp Clin Res 22: 17–24.
[26]
Calabrese V, Randazzo G, Ragusa N, Rizza V (1998) Long-term ethanol administration enhances age-dependent modulation of redox state in central and peripheral organs of rat: protection by metadoxine. Drugs Exp Clin Res 24: 85–91.
[27]
Bedda S, Laurent A, Conti F, Chereau C, Tran A, et al. (2003) Mangafodipir prevents liver injury induced by acetaminophen in the mouse. J Hepatol 39: 765–772.
[28]
Ferret PJ, Hammoud R, Tulliez M, Tran A, Trebeden H, et al. (2001) Detoxification of reactive oxygen species by a nonpeptidyl mimic of superoxide dismutase cures acetaminophen-induced acute liver failure in the mouse. Hepatology 33: 1173–1180.
[29]
Koo A, Komatsu H, Tao G, Inoue M, Guth PH, et al. (1992) Contribution of no-reflow phenomenon to hepatic injury after ischemia-reperfusion: evidence for a role for superoxide anion. Hepatology 15: 507–514.
[30]
Rudiger HA, Kang KJ, Sindram D, Riehle HM, Clavien PA (2002) Comparison of ischemic preconditioning and intermittent and continuous inflow occlusion in the murine liver. Ann Surg 235: 400–407.
[31]
Skjold A, Vangberg TR, Kristoffersen A, Haraldseth O, Jynge P, et al. (2004) Relaxation enhancing properties of MnDPDP in human myocardium. J Magn Reson Imaging 20: 948–952.
[32]
Alexandre J, Nicco C, Chereau C, Laurent A, Weill B, et al. (2006) Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir. J Natl Cancer Inst 98: 236–244.
[33]
Baker MA, Cerniglia GJ, Zaman A (1990) Microtiter plate assay for the measurement of glutathione and glutathione disulfide in large numbers of biological samples. Anal Biochem 190: 360–365.
[34]
Rojo AI, Salinas M, Martin D, Perona R, Cuadrado A (2004) Regulation of Cu/Zn-superoxide dismutase expression via the phosphatidylinositol 3 kinase/Akt pathway and nuclear factor-kappaB. J Neurosci 24: 7324–7334.
[35]
Zhou LZ, Johnson AP, Rando TA (2001) NF kappa B and AP-1 mediate transcriptional responses to oxidative stress in skeletal muscle cells. Free Radic Biol Med 31: 1405–1416.
[36]
Rudiger HA, Graf R, Clavien PA (2003) Sub-lethal oxidative stress triggers the protective effects of ischemic preconditioning in the mouse liver. J Hepatol 39: 972–977.
[37]
Sindram D, Rudiger HA, Upadhya AG, Strasberg SM, Clavien PA (2002) Ischemic preconditioning protects against cold ischemic injury through an oxidative stress dependent mechanism. J Hepatol 36: 78–84.
[38]
Yuan GJ, Ma JC, Gong ZJ, Sun XM, Zheng SH, et al. (2005) Modulation of liver oxidant-antioxidant system by ischemic preconditioning during ischemia/reperfusion injury in rats. World J Gastroenterol 11: 1825–1828.
[39]
Llacuna L, Mari M, Lluis JM, Garcia-Ruiz C, Fernandez-Checa JC, et al. (2009) Reactive oxygen species mediate liver injury through parenchymal nuclear factor-kappaB inactivation in prolonged ischemia/reperfusion. Am J Pathol 174: 1776–1785.
[40]
Yadav SS, Gao W, Harland RC, Clavien PA (1998) A new and simple technique of total hepatic ischemia in the mouse. Transplantation 65: 1433–1436.
