Intravenous administration of recombinant tPA remains the only FDA-approved and the most beneficial proven intervention for emergency treatment of stroke. However, short treatment time window, hemorrhagic transformation, poor thrombolytic perfusion rate, and neurotoxicity comprise the major limitations to the application. In this proposal, we hypothesize that recombinant Annexin A2 protein (rA2) will lower the required dose of tPA for reperfusion, while enhancing thrombolytic efficacy, and attenuating intracerebral hemorrhagic transformation. By doing so, it will prolong therapeutic time windows and improve long-term outcomes. The molecular basis for our idea is that annexin A2 accelerates the generation of clot-dissolving plasmin by assembling a fibrinolytic complex with tPA and the plasmin precursor plasminogen. Our pilot data are promising. We now propose three aims to investigate the mechanisms involved in this new combination therapy.
In Aim 1, we will study thrombolytic efficacy of rA2 plus low dose tPA combination treated at 4 hrs after focal embolic stroke in rats with MR angiography to determine recanalization and reocclusion, MRI CBF to map cerebral blood flow;and MRI measurements of cerebral blood volume (CBV), microvascular volume (MVV), and vessel size index (VSI) to quantify vascular responses to thrombolytic agents and vasodilators.
In Aim 2, we will investigate effects of rA2 plus low dose tPA combination therapy on neurovascular matrix proteolysis and BBB leakage treated at 4 hrs after focal embolic stroke of rats. The development of brain infarction, edema and hemorrhagic transformation will be measured and correlated with temporal profiles of MMP-9 activity, proteolytic degradation of extracellular matrix components and BBB leakage.
In Aim 3, we will assess long term outcomes of rA2 plus low dose tPA combination treated at 4 hrs after stroke. Rats will be followed over 4 weeks with a battery of behavioral tests. At the end, brains are removed for H&E lesion size measurement, cerebral vessel density and tissue recovery factors VEGF, Ang-1 expression will be examined. Low-dose tPA plus rA2 will be compared with rA2 alone, low-dose and high-dose tPA alone, and vehicle saline control. If successful, these proposed experiments should provide new insight of how rA2 plus low dose tPA improve tPA stroke treatment and may ultimately yield a novel combination approach to optimize tPA-based thrombolytic stroke therapy. We believe our proposal should be directly relevant for PA-07-233, "Multidisciplinary Translational Research in Critical Care" (R01).
Intravenous administration of tPA is the only FDA-approved emergency treatment for ischemic stroke. Mainly because the risk of brain bleeding, only 2-5% stroke patients receive tPA in USA. Here we propose a new combination therapy of annexin A2 plus tPA, it will generate more beneficial thrombolytic enzyme plasmin with much lower tPA dose. By doing so, the combination will enhance clot lysis for blood flow restorage and reduce the risk of bleeding. These effects should prolong treatment window and improve long-term outcomes.
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|Jiang, Yinghua; Fan, Xiang; Yu, Zhanyang et al. (2015) Low dose tPA plus annexin A2 combination attenuates tPA delayed treatment-associated hemorrhage and improves recovery in rat embolic focal stroke. Neurosci Lett 602:73-8|
|Jiang, Yinghua; Fan, Xiang; Yu, Zhanyang et al. (2015) Combination Low-Dose Tissue-Type Plasminogen Activator Plus Annexin A2 for Improving Thrombolytic Stroke Therapy. Front Cell Neurosci 9:397|
|Wang, Xiaoshu; Fan, Xiang; Yu, Zhanyang et al. (2014) Effects of tissue plasminogen activator and annexin A2 combination therapy on long-term neurological outcomes of rat focal embolic stroke. Stroke 45:619-22|
|Fan, Xiang; Lo, Eng H; Wang, Xiaoying (2013) Effects of minocycline plus tissue plasminogen activator combination therapy after focal embolic stroke in type 1 diabetic rats. Stroke 44:745-52|
|Dai, Haibin; Yu, Zhanyang; Fan, Xiang et al. (2013) Dysfunction of annexin A2 contributes to hyperglycaemia-induced loss of human endothelial cell surface fibrinolytic activity. Thromb Haemost 109:1070-8|
|Fan, Xiang; Ning, Mingming; Lo, Eng H et al. (2013) Early insulin glycemic control combined with tPA thrombolysis reduces acute brain tissue damages in a focal embolic stroke model of diabetic rats. Stroke 44:255-9|
|Yu, Zhanyang; Poppe, Jessica L; Wang, Xiaoying (2013) Mitochondrial mechanisms of neuroglobin's neuroprotection. Oxid Med Cell Longev 2013:756989|
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|Fan, Xiang; Qiu, Jianhua; Yu, Zhanyang et al. (2012) A rat model of studying tissue-type plasminogen activator thrombolysis in ischemic stroke with diabetes. Stroke 43:567-70|
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