Role of Oleanolic acid in maintaining BBB integrity by targeting p38MAPK/VEGF/Src signaling pathway in rat model of subarachnoid hemorrhage

Vasogenic brain edema after subarachnoid hemorrhage (SAH) is an independent risk factor for death and poor prognosis. Disruption of the blood-brain barrier (BBB) is the main cause of vasogenic brain edema induced by SAH. Oleanolic acid (OA) is a natural pentacyclic triterpenoid with various biological functions. Previous studies have shown that prophylactic administration of OA could prevent the BBB disruption in autoimmune encephalomyelitis mice. In this context, we speculate that OA may play a neuroprotective role by protecting the integrity of the BBB and reducing vasogenic cerebral edema after SAH. To validate this hypothesis, a SAH model was established on Sprague Dawley rats using a standard intravascular puncture model. The effects of OA on various physiological indexes were observed, including SAH grades, mortality, neurological function score, brain edema and BBB permeability. Related proteins of the brain endothelial cell junction complex were also detected, including tight junctions (TJs) and adherent junctions (AJs). Results showed that OA significantly reduced the permeability of BBB and relieved brain edema by increasing protein expression of TJs and AJs, and decreased the SAH grades by increasing the protein expression of heme oxygenase-1 (HO-1) in SAH rats. Additionally, we found OA could inhibit up-regulation of VEGF and the phosphorylation of p38 mitogen-activated protein kinase (MAPK), and suppress p38MAPK/VEGF/Src signaling pathway which involved in BBB disruption following SAH. From the experimental results, we speculate that OA effectively alleviated SAH-induced vasogenic edema by targeting p38 MAPK/VEGF/Src axis.