Icariside II, a phosphodiesterase 5 inhibitor, attenuates brain injury in focal cerebral ischemia/reperfusion rats: Involvement of inhibition of GSK‐3β‐mediated activation of autophagy

Abstract

Cerebral ischemia/reperfusion (I/R) is always exacerbated neuronal damage when timely restoring cerebral blood flow after ischemia stroke. Cerebral I/R results in excessive autophagy and leads to neuronal demise. The present study was designed to investigate the role of autophagy during ICS II‐mediated neuroprotection on cerebral I/R in vivo and in vitro. Here, we found that ICS II not only protected against middle cerebral artery occlusion‐induced injury in rats, but also attenuated primary cortical neurons injury upon oxygen‐glucose deprivation. Moreover, autophagy was activated as evidenced by triggered autophagic influx and increased ATG expressions after stimulation of cerebral I/R. However, ICS II signifcantly inhibited excessive autophagy as evidenced by repressing autophagic flux, combined with decreasing ATG expressions including LC3 II, Beclin 1, ATG5 and ATG7. Interestingly, ICS II, a PDE5 inhibitor, not only restored cGMP/PKG pathway, but also inactivated GSK‐3β through mediating phosphorylation at tyr216 and ser9. Most intrugingly, siGSK‐3β obviously promoted the beneficial effect of ICS II, which further confirmed that the neuroprotective mechanism of ICS II is, at least in partly, through inactivating GSK‐3β. Furthermore, we reveled that the cGMP/PKG pathway acts as the upstream of GSK‐3β inactivation in the inhibitory effect of ICS II on cerebral I/R‐induced autophagic neuronal death, as evidenced by GSK‐3β inhibitor or PKG inhibitor in vitro. Most importantly, the findings demonstrated that ICS II protected against cerebral I/R‐induced injury via mediating PKG/GSK‐3β/autophagy axis. This study will raise the possibility that ICS II may be exploited into a potent PDE 5 inhibitor against ischemia stroke.Support or Funding InformationThis work was supported by Natural Science Foundation of China Natural Science Foundation of China (Grant No. 81560666), Program for excellent young talents of Zunyi Medical University (Grant No. 15zy‐002), Science and Technology Innovation Talent Team of Guizhou Province (Grant No.20154023), The hundred level of high‐level innovative talents in Guizhou Province (Grant No. QKHRCPT 20165684), and Program for Changjiang Scholars and Innovative Research Team in University, China (Grant No. IRT_17R113).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.