Phosphodiesterase-4 inhibition confers a neuroprotective efficacy against early brain injury following experimental subarachnoid hemorrhage in rats by attenuating neuronal apoptosis through the SIRT1/Akt pathway

Abstract

Phosphodiesterase-4 (PDE4) plays a fundamental role in a range of central nervous system (CNS) insults, however, the role of PDE4 in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The current study was designed to investigate the role of PDE4 in EBI after SAH and explore the potential mechanism. The SAH model in Sprague-Dawley rat was established by endovascular perforation process. Rats were randomly divided into: sham group, SAH + vehicle group, SAH + rolipram (PDE4 inhibitor) group, SAH + rolipram + sirtinol (SIRT1 inhibitor) group and SAH + rolipram+MK2206 (Akt inhibitor) group. Mortality, SAH grades, neurological function, brain edema, immunofluorescence staining and western blotting were performed. Double fluorescence labeling staining indicated that PDE4 was located predominately in neurons after SAH. Rolipram reduced brain edema, improved neurological function in the rat model of SAH. Moreover, rolipram increased the expression of Sirtuin1 (SIRT1) and up-regulated the phosphorylation of Akt, which was accompanied by the reduction of neuronal apoptosis. Administration of sirtinol inhibited the phosphorylation of Akt. Moreover, all the beneficial effects of rolipram against SAH were abolished by both sirtinol and MK2206. These data indicated that PDE4 inhibition by rolipram protected rats against EBI after SAH via suppressing neuronal apoptosis through the SIRT1/Akt pathway. Rolipram might be an important therapeutic drug for SAH.