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

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

Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB and BDNF

In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD

Inhibition of calpain-regulated p35/cdk5 plays a central role in sildenafil-induced protection against chemical hypoxia produced by malonate

AbstractPhosphodiesterase 5 (PDE5) inhibitors 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 (1.5mg/kg by mouth (p.o.)), given 30min before malonate (1.5μmol/2μL), significantly decreased the lesion volume caused by this toxin. This protective effect can be probably related to the inhibition of excitotoxic pathways. Thus, malonate induced the activation of the calcium-dependent protease, calpain and the cyclin-dependent kinase 5, cdk5; which resulted in the hyperphosphorylation of tau and the cleavage of the protective transcription factor, myocyte enhancer factor 2, MEF2. All these effects were also significantly reduced by sildenafil pre-treatment, suggesting that sildenafil protects against malonate-induced cell death through the regulation of the calpain/p25/cdk5 signaling pathway. Similar findings were obtained using inhibitors of calpain or cdk5, further supporting our contention. Sildenafil also increased MEF2 phosphorylation and Bcl-2/Bax and Bcl-xL/Bax ratios, effects that might as well contribute to prevent cell death. Finally, sildenafil neuroprotection was extended not only to rat hippocampal slices subjected to oxygen and glucose deprivation when added at the time of reoxygenation, but also, in vivo when administered after malonate injection. Thus, the therapeutic window for sildenafil against malonate-induced hypoxia was set at 3h