RT Journal Article
T1 Inhibition of calpain-regulated p35/cdk5 plays a central role in sildenafil-induced protection against chemical hypoxia produced by malonate
A1 Barros-Miñones, Lucía
A1 Martín De Saavedra Álvarez De Uribarri, María Dolores
A1 Perez-Alvarez, Sergio
A1 Orejana, Lourdes
A1 Suquía, Verónica
A1 Goñi-Allo, Beatriz
A1 Hervias, Isabel
A1 López, Manuela
A1 Jordan, Joaquin
A1 Aguirre, Norberto
A1 Puerta, Elena
AB Phosphodiesterase 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 (1.5 mg/kg by mouth (p.o.)), given 30 min before malonate (1.5 μmol/2 μL), 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 3 h.
PB Elsevier
SN 0925-4439
YR 2013
FD 2013
LK https://hdl.handle.net/20.500.14352/92821
UL https://hdl.handle.net/20.500.14352/92821
LA eng
NO Barros-Miñones L, Martín-de-Saavedra D, Perez-Alvarez S, Orejana L, Suquía V, Goñi-Allo B, et al. Inhibition of calpain-regulated p35/cdk5 plays a central role in sildenafil-induced protection against chemical hypoxia produced by malonate. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2013;1832:705–17. https://doi.org/10.1016/j.bbadis.2013.02.002.
NO Ministerio de Ciencia e Innovación (España)
DS Docta Complutense
RD 4 abr 2025