The Role And Mechanism Of Dopamine-mediated Endogenous TPA In Blood-brain Barrier Injury Induced By Acute Cerebral Ischemia

Hemorrhagic transformation(HT),the most serious complication in thrombolytic therapy for acute ischemic stroke,occurs as a result of failure of the blood brain barrier(BBB)integrity.Disruption of the BBB integrity at the early stage of ischemia is becoming a critical target to reduce HT.Our recent studies showed that 2 h of ischemia caused BBB damage in non-infarcted ventral striatum.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 is infusion of dopamine l receptor(DlR)agonist SKF38393 significantly increase endogenous tissue plasminogen activator(tPA)activation in ventral striatum.Therefore,we hypothesized that acute cerebral ischemia caused a significant increase of dopamine in ventral striatum,which caused BBB damage by activating endogenous tPA.Objective:This study represent a new therapeutic target for protecting BBB,and may help alleviate HT following thrombolysis after ischemia stroke.Methods:Rats weighing 270 to 290 g were subjected to 2-h MCAO using the intraluminal suture occlusion model.Rats were divided into four groups:(1)Vehicle group(2)Neuroserpin group(tPA inhibitor)(3)SCH23390 group(dopamine 1 receptor antagonist)(4)YC-1 group(HIF-la inhibitor).EB and IgG leakage was used to evaluate BBB permeability.The expression of occludin was detected by immunofluorescence and Western blot.Results:1.There was an increase of endogenous tissue tPA in BBB damage area and intra-striatum infusion of tPA inhibitor neuroserpin,significantly alleviated ischemia-induced BBB damage.2.The intra-striatum infusion of PIR antagonist SCH23390 significantly.decreased ischemia-induced uprcgulation of endogenous tPA,accompanied by decrease of BBB damage and occludin degradation.3.The inhibition of HIF-la with inhibitor YC-1 significantly decreased acute ischemia-induced endogenous tPA upregulation and BBB damage.Conclusions:Our results indicate that up-regulation of HIF-la in the acute ischemic phase increases the interaction of dopamine with DIR,which in turn activates endogenous tPA to disrupt BBB.By studying the BBB integrity at the early stage of ischemia,we hope to find an effective treatment strategy,and provide a theoretical basis for prolonging the thrombolysis time window of tPA and reducing the hemorrhagic transformation.