necrox-7 and Reperfusion-Injury

Necrotic cell death is common in a wide variety of pathologic conditions, including ischemia-reperfusion (IR) injury. The aim of this study was to develop an IR injury-induced hepatic necrosis model in dogs by means of selective left hepatic inflow occlusion and to test the efficacy of a new chemical compound, NecroX-7, against the IR injury-induced hepatic damage.. A group of male Beagle dogs received intravenous infusions of either vehicle or different doses of NecroX-7 (1.5, 4.5, or 13 mg/kg) for a 20-minute period before a 90-minute left hepatic inflow occlusion followed by reperfusion.. The gross morphology in the NecroX-7-treated groups after occlusion appeared to be less congested and less swollen than that in vehicle-treated control group. Circulating alanine transaminase and aspartate transaminase levels in the control group were elevated during the course of IR, and were effectively blocked in the 4.5 and 13 mg/kg NecroX-7-treated groups. The serum levels of high-mobility group box 1 protein showed a peak at 8 hours after occlusion in control group, and this elevation was significantly blunted by 4.5 mg/kg NecroX-7 treatment. Histologic analysis showed a marked ischemia or IR injury-induced hepatocytic degenerations, sinusoidal and portal vein congestions, and inflammatory cell infiltrations in the control group, whereas the treatment groups showed significantly diminished histopathology in a dose-dependent manner.. These results demonstrated that NecroX-7 attenuated the hepatocyte lethality caused by hepatic IR injury in a large animal setting. We conclude that NecroX-7 may provide a wide variety of therapeutic options for IR injury in human patients.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Dogs; Dose-Response Relationship, Drug; HMGB1 Protein; Liver; Liver Circulation; Male; Necrosis; Organic Chemicals; Portal Vein; Reperfusion Injury

The liver is susceptible to ischemia-reperfusion (IR) injury during inflow occlusion for hepatectomy. There is no effective pharmacologic agent available to prevent the release of high-mobility-group box 1 (HMGB1) or to ameliorate IR injury. This pilot study sought to develop a model in beagle dogs for the purpose of testing the efficacy of a necrosis modulator, necrox-7, to prevent hepatic IR injury in beagle dogs.. Six male beagle dogs were randomly assigned to the control group (group A; n = 3) or the treatment group (group B; n = 3). Under general anesthesia, group B received intravenous infusion of necrox-7 (13 mg/kg over 20 minutes) followed by 60 minutes of left hepatic inflow occlusion and 60 minutes of reperfusion. Both groups were tested for serum biochemicals, hematology values, liver biopsies, and plasma HMGB1 levels over a 48-hour period.. The maximum alanine transferase (ALT), aspartate transferase (AST), and lactate dehydrogenase (LDH) levels among group A versus group B were: ALT 868.3 ± 337.4 IU/L vs 274.3 ± 72.6 IU/L (P = .041); AST 1,024.7 ± 246.5 IU/L vs 505.3 ± 66.7 IU/L (P = .024); and LDH 962.7 ± 226.2 IU/L vs 552.7 ± 62.4 IU/L (P = .039). Liver biopsy demonstrated marked necrosis and inflammatory infiltrates in group A, whereas group B showed little evidence of IR injury. The plasma HMGB1 concentration was significantly lower among group B versus A.. This pilot study developed a hepatic IR injury model, demonstrating that necrox-7 reduced hepatic necrosis secondary to IR injury in a large animal setting.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Biomarkers; Biopsy; Disease Models, Animal; Dogs; HMGB1 Protein; Infusions, Intravenous; L-Lactate Dehydrogenase; Liver; Male; Necrosis; Organic Chemicals; Pilot Projects; Protective Agents; Reperfusion Injury; Time Factors