Salvianolic acid A attenuates cerebral ischemia/reperfusion injury induced rat brain damage, inflammation and apoptosis by regulating miR-499a/DDK1

Background and objectives: Salvianolic acid A (SAA) is a main component derived from Salvia miltiorrhiza and has been revealed to protect against cerebral ischemia/reperfusion injury (CIRI). The present study was designed to evaluate the neuroprotective role of SAA in CIRI and explore its underlying mechanism in vivo and in vitro.

Methods: To determine the neuroprotective effects of SAA on CIRI in vivo, the middle cerebral artery occlusion (MCAO) rat model was established. Besides, oxygen-glucose deprivation/reperfusion (OGD/R)-induced PC12 cells were used to analysis the effects of SAA on CIRI in vitro. Neurological deficit score, brain water content, cell proliferation, apoptosis and inflammation were measured. In addition, the effects of SAA on miR-449a/DKK1 and Wnt/β-catenin pathway were evaluated.

Results: The level of miR-449a was decreased in MCAO rat models as well as OGD/R-induced PC-12 cells. SAA could significantly inhibit cell apoptosis and inflammation both in MCAO rat model and OGD/R-induced PC-12 cells. Also, SAA inhibited cerebral edema and promoted PC12 cell proliferation. Besides, we proved that the 3'-UTR of DKK1 mRNA is the target of miR-449a. Furthermore, we demonstrated that SAA could activate Wnt/β-catenin pathway and play the neuroprotective role by regulating miR-499a/DDK1.

Conclusion: Taken together, these results suggest that SAA could increase miR-449a level and then inhibit DDK1 expression to activate Wnt/β-catenin pathway, leading to the alleviation of cerebral ischemia/reperfusion injury in vivo and in vitro.

Keywords: Salvianolic acid A; apoptosis; brain damage; cerebral ischemia/reperfusion injury; inflammation; miR-499a/DDK1.