ИСТИНА

The toxic effects of aminoglycoside antibiotics are realized via stimulating intercellular reactive oxygen species (ROS) overproduction. Oxidative damage of mitochondria results in the opening of mitochondrial permeability transition pore (MPTP). The signaling prevents opening of MPTP are know as preconditioning (PC) phenomenon. PC signaling pathways are converged on glycogen synthase kinase 3β (GSK3β) and results in its inhibition by phosphorylation. The aim of the study was to investigate whether mitochondria-targeted antioxidant SkQR1 and δ-opyoid receptor agonist (dalargin) and GSK3β inhibitor (LiCl) are able to prevent gentamycin toxicity.In vitro gentamycin caused kidney cells death during 24 h. Preincubation with 50 nM SkQR1 for 24 h significantly increased the survival of the cells. In vivo gentamycin application resulted in pronounced nephrotoxicity (3.6-fold increase of creatinine concentration), marked mortality. SkQR1 administration (i.p. 100 nmol/kg) 3 h before each gentamycin injection mitigated renal failure (creatinine dropped from 293 ± 31 to 169 ± 23 μM) and diminished mortality (from 35% to 17% on 20th day). SkQR1 also normalized renal erythropoietin level lowered after gentamycin treatment. Thus, administration of SkQR1 was found to induce PC signaling in the kidney (increase in erythropoietin and p-GSK3b content). The rise in p-GSK3b was also observed after i.p. injection of δ-opyoid receptor agonist dalargin or mood-stabilizing drug LiCl. Pretreatment with dalargin (i.p. 50 mg/kg) or LiCl (i.p. 30 mg/kg) decreased the severity of renal failure (creatinine dropped down from 394 ± 35 to 205 ± 47.0 and 229 ± 48 μM, respectively). Conclusions: We conclude that mitochondria-targeted antioxidant SkQR1 effectively prevented nephrotoxicity of gentamycin. Partially this protective effect could be referred to induction of PC signaling. Moreover, different compounds that inhibits GSK3b thus protecting mitochondria, such as LiCl and dalargin, may serve as promising agents for preventing negative consequences of aminoglycoside therapy