Protection of cellular and mitochondrial functions against liver ischemia by N-benzyl-N'-(2-hydroxy-3,4-dimethoxybenzyl)-piperazine (BHDP), a sigma1 ligand.

We investigated the antiischemic properties of a new compound N-benzyl-N'-(2-hydroxy-3,4-dimethoxybenzyl)-piperazine (BHDP), having high affinity and selectivity for the sigma(1) receptor, in two different models of ischemia. The first was an experimental model of rat liver normothermic ischemia-reperfusion. Rats were pretreated with different doses of BHDP (0.5, 2.5 or 10 mg/kg/day, or solvent alone) and subjected to 90 min normothermic ischemia followed by either 30 or 120 min reperfusion. The second model was a hypothermic model of ischemia in which livers were incubated for 24 h at 4 degrees C in a preservation solution in the absence or presence of increasing BHDP concentrations (0.5, 2.5 or 10 microg/ml). These different ischemic conditions induced huge alterations in hepatocyte functions (membrane leakage of alanine aminotransferase and aspartate aminotransferase, decreased metabolic capacities evaluated by the ability of the liver to transform lidocaine, alterations of mitochondrial functions characterized by a decrease in ATP synthesis and the appearance of histological damages). Pretreatment of rats with BHDP alleviated these deleterious ischemia-reperfusion effects in a dose-dependent manner at both the cellular and mitochondrial levels. The protection of mitochondrial functions was almost complete at a dosage of 10 mg/kg/day during normothermic ischemia and 10 microg/ml in the preservation liquid during hypothermic ischemia. In addition, BHDP significantly reduced the histological damage. These data demonstrate that BHDP protects liver against the deleterious effects of ischemia-reperfusion and suggest that sigma(1) receptors play an important role in the protective effect.