S3B-2 D1 Receptor-Mediated Endogenous tPA Upregulation Contributes to Acute Blood Brain Barrier Damage

Background:Disruption of the blood brain barrier(BBB)integrity at the early stage of ischemia is becoming a critical target to reduce hemorrhage transformation(HT)because of the potential to predict HT.However,the mechanism underlying early BBB damage is not very clear.It was reported that after acute ischemia,there was a significant increase of dopamine release in striatum where we have reported BBB damage as well as upregulation of HIF-1αafter 2 h ischemia.Objective:In current study,we aimed to investigate the role of dopamine signal pathway in BBB damage after acute ischemia using in vivo rat middle cerebral artery occlusion(MCAO)model.Results:Our data showed that there was an increase of endogenous tissue plasminogen activator(tPA)in BBB damage area and intra-striatum infusion of tPA inhibitor neuroserpin,significantly alleviated ischemia-induced BBB damage.In addition,intra-striatum infusion of D1 antagonist SCH23390 significantly decreased ischemia-induced upregulation of endogenous tPA,accompanied by decrease of BBB damage and occludin degradation.More important,inhibition of HIF-1 with inhibitor YC-1 significantly decreased acute ischemia-induced endogenous tPA upregulation and BBB damage.Conclusion:Taken together,our data demonstrate that acute ischemia disrupted BBB through activation of endogenous tPA via HIF-1 upreguationinduced dopamine increase,thus representing a new therapeutic target for protecting BBB,and may help alleviate HT following thrombolysis after ischemia stroke.