Efecto neuroprotector del sildenafilo frente a la isquemia química inducida por la toxina mitocondrial malonato

Abstract

Phosphodiesterase 5 inhibitors (PDE5i) have recently been reported to exert beneficial effects against ischemia-reperfusion injury in several organs but their neuroprotective effects in brain stroke models are scarce. The present study was undertaken to assess the effects of sildenafil against cell death caused by intrastriatal injection of malonate, an inhibitor of succinate dehydrogenase; which produces both energy depletion and lesions similar to those seen in cerebral ischemia. Our data demonstrate that sildenafil (1.5 mg/kg p.o.), given 30 min before malonate (1.5 ìmol/2 ìl), significantly decreased the lesion volume caused by this toxin. This protective effect cannot be attributed to any effect on reactive oxygen species production. By contrast, our results suggest that inhibition of malonate-induced activation of calpain/p25/cdk5 and ASK-1/MKK3/6/p38 pathways play a key role in the neuroprotective effects of this PDE5i. Sildenafil also increased the expression of two antiapoptotic proteins, namely Bcl-2 and Bcl-xL, as well as the phosphorylation of the prosurvival factor MEF2; effects that might, as well, contribute to prevent the cell death caused by malonate. The neuroprotective effect of sildenafil was not only preventive but also therapeutic. Thus, sildenafil protected hippocampal slices subjected to oxygen and glucose deprivation (OGD) when administered during reoxygenation and also reduced tissue damage caused by malonate if administered up to 3 hours after the injection of the mitochondrial toxin.