Abstracts

N1-guanyl-1,7-diaminoheptane (GC7), an inhibitor of eIF5A,exhibits anti-inflammatory features and promotes anoxic/ischemic tolerance.Thus, GC7 pretreatment could be useful in order to protect organs submitted toischemia before transplantation in heart-beating donors.Methods: Using a pig brain death donation preclinical model, we carried outthe in vivo evaluation of GC7 pre-treatment (3 mg/kg iv bolus), after braindeath, at the beginning of the 4 h-reanimation, after which one kidney wascollected, cold-stored (18-h in UW), and allo-transplantated in a doublenephrectomizedrecipient. Groups were defined as follows (n = 6 per group):healthy (Control), untreated Brain death (BD) and GC7-treated BD (GC7).Results: R1. At the end of 4 h-reanimation, GC7 decreased (80–100%,p < 0.05) BD-increased markers: (i) eIF5A hypusination, (ii) tissue levels ofreactive oxygen species markers (CellRox staining and Aconitase), (iii) tissuelevels of nitrotyrosine, and (iv) the mitochondrial-dependent apoptosis pathway(Bax/Bcl-2 proapoptotic ratio, Caspase-9). In addition, GC7 increased (2 to 6-fold, p < 0.05) the expression of anti-oxidant proteins (SOD2 and HO-1, as wellas PGC-1a, Nrf2, and total & p-Sirtuin1 & 3). R2. At the end of cold storage,GC7 treatment normalized BD-dependent decrease of SOD2 and HO-1proteins expression (p < 0.05). In addition, GC7 significantly restored the BDdependentincrease of the Bax/Bcl-2 (proapoptotic) ratio (p < 0.05).Conclusion: After the reanimation phase, preventively given GC7 provedprotective for kidneys against brain death-induced injuries; during the coldstorage phase, GC7 appeared to preserve antioxidant defences and to protectmitochondria. Early and long-term, post-transplantation propagation ofobserved protective effects are currently evaluated