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 mec...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.展开更多
基金This work was supported by the Ministry of Science and Technology of China(No.2006CB500807)the Program for Changjiang Scholars and Innovative Research Team in University from Ministry of Education of China the National Natural Science Foundation of China(No.30225023,30430240,30611120530).
文摘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.
