Mangafodipir Protects against Hepatic Ischemia-Reperfusion Injury in Mice

Abstract

Introduction and AimMangafodipir 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.MethodsMice 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.ResultsMangafodipir 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.ConclusionsMangafodipir is a potential new preventive treatment for hepatic ischemia-reperfusion injury.

Pretreatment with Mangafodipir Improves Liver Graft Tolerance to Ischemia/Reperfusion Injury in Rat

“…Taken together, our data suggest that mitochondria might also be an important target through which MnDPDP exerts its cytoprotective effect. Our findings support previous data regarding protective effects of MnDPDP on cardiac dysfunction after reperfusion [22], [60] and liver injury [19], [23] through prevention of mitochondrial apoptotic cascade and caspase-3 activation.…”

“…This property is related to the fodipir moiety of MnDPDP, a chelate of manganese resulting from the condensation of two pyridoxal 5′-phosphate molecules [21]. This fodipir moiety binds to the pyridoxal 5′-phosphate receptor on hepatocytes and ensures a high intrahepatic concentration of MnDPDP through its specific biding to vitamin B6 receptors expressed by hepatocytes [23].…”

“…This effect supports an antioxidant action of MnDPDP in the post-ischemic liver tissue. Using different models of stress, previous studies indicate that a protective effect of MnDPDP is associated with catalase-, SOD- and GSH reductase-like properties, allowing this compound to act at multiple steps of the ROS cascade [19], [20], [22], [23]. It has also been suggested that MnDPDP protects leukocytes from apoptosis induced either by H 2 O 2 or by chemotherapeutic agents like oxaliplatin and paclitaxel [44], and prevent Huh-7 hepatoma cell death induced by H 2 O 2 and superoxide anion [19].…”

“…Preventive administration of MnDPDP was associated with significant liver injury decrease in a mouse model of acetaminophen-induced acute liver failure [19]. More recently, the same group confirmed the protective properties of MnDPDP using a mouse model of hepatic I/R injury [23]. Besides, it has been reported that MnDPDP decreases myocardial damage in ischemic porcine myocardium [20]–[22].…”

Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

“…Vitamin B6 is known for its ability to maintain normal neurological functions and for its neuroprotective activity (15). In addition, given that mangafodipir is endowed with SOD-, catalase-, and glutathione reductase-like (GR-like) properties, it can target multiple steps of the ROS cascade by detoxifying superoxide anions and hydrogen peroxide and by restoring GSH (16,17). Moreover, this molecule is known to cross the cell membrane, and we have already shown its ability to improve the therapeutic index of oxaliplatin (18).…”