Activation of the Epac/Rap1 signaling pathway alleviates blood-brain barrier disruption and brain damage following cerebral ischemia/reperfusion injury

Blood brain barrier (BBB) destruction plays a key role in ischemia stroke, including promoting BBB leakage and brain edema, and leads to unfavorable patient prognosis. Epac/Rap1 signaling pathway is important in mediating endothelial cell barrier function. This study will investigate the regulatory role of Epac/Rap1 signaling pathway in BBB disruption after cerebral ischemia/reperfusion (CI/R) injury. CI/R model was induced by 90 min of transient middle cerebral artery occlusion (MCAO) in male C57BL/6J mice. Injection of Epac/Rap1 signaling pathway agonist was performed half an hour before the MCAO operation. The results showed that CI/R injured the tight connection of BBB and evoked the suppression of the Epac/Rap1 signaling pathway. Based on Epac activation with a cAMP analogue, 8-CPT could improve BBB disfunction by increasing the expression of tight junction protein and reducing the formation of stress fibers. In addition, 8-CPT could ameliorate neurobehavioral disorders, cerebral edema, and cerebral infarction volume in MCAO mice. Moreover, inhibition of Epac pathway with Rap1 inhibitor GGTI298 and Rac1 inhibitor NSC23766 could aggravate the damage of BBB and cerebral injury accordingly. Our results indicate that, the activation of Epac/Rap1 signaling pathway has neuroprotective effects on CI/R damaged brain, through the recovery of BBB.

8-CPT-2ʹ-O-Me-cAMP; Blood-brain barrier; Cerebral ischemia/reperfusion; Epac/Rap1 signaling pathway; Filamentous actin; Tight junction.