ИСТИНА

The toxic effects of aminoglycoside antibiotics are realized via stimulating intracellular reactive oxygen species (ROS) overproduction. Oxidative damage of mitochondria results in the induction of mitochondrial permeability transition pore (MPTP). Activation of signaling pathways that prevents opening of MPTP is known 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, -opyoid receptor agonist dalargin and GSK3β inhibitor LiCl are able to prevent gentamycin nephrotoxicity. Male outbred rats were treated with gentamycin (i.p. 160 mg/kg/day) for 6 days. Protocol resulted in pronounced nephrotoxicity (3.6-fold increase of serum creatinine ), marked mortality and decrement in renal erythropoietin (EPO) content. SkQR1 administration (i.p. 100 nmol/kg) 3 h before each gentamycin injection mitigated renal failure, diminished mortality and normalized EPO level. The single injection of SkQR1 to intact rats was found to induce PC signaling in the kidney: 1.8-fold increase in EPO content and 2-fold increase in p-GSK3 content 3 h and 24 h after SkQR1 injection respectively. The rise in p-GSK3 content was also observed after i.p. injection of δ-opyoid receptor agonist dalargin (i.p. 50 g/kg) or mood-stabilizing drug LiCl (i.p. 30 mg/kg). Single gentamicyn (i.p. 160 mg/kg) injection caused the 10-fold increase of ROS production in kidney, detected by DCF-DA staining. Dalargin or LiCl mitigated ROS production (15% and 35% decrease respectively) when administrated 3 h before gentamicyn. The long-term gentamicyn treatment resulted in accumulation of carbonylated proteins in the kidney (measured by OxyBlot) and renal function impairment. Pretreatment with dalargin or LiCl before each gentamycin injection resulted in 50% and 35% decrement of carbonylated proteins signal intensity and in reduced kidney injury. 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 inhibit GSK3 thus protecting mitochondria, such as LiCl and dalargin, may serve as promising agents for preventing negative consequences of aminoglycoside therapy. The work was supported by RFBR grants 14-04-00300 and 14-04-00542.