Abstract 129: PAK01: A Synthesized Small Molecule That Enhances Reperfusion, Neuroprotection and Avoids Hemorrhagic Transformation in Rodent Models of Thromboembolic Stroke
Tissue-type plasminogen activator (t-PA) is currently the only approved drug by the US FDA for treating the acute ischemic stroke within 3 hours of symptom onset, despite the fact that the therapy may cause serious hemorrhagic transformations and neurotoxicity that leads to enhanced brain injury. Here we developed a synthesized small pseudopeptide, PAK01, to address efficacy and safety issues observed in t-PA treatment in acute ischemic stroke by covalently combining a free radical scavenger, a thrombus-targeted platelet aggregation inhibitor and a non-t-PA thrombolytic peptide into a single structure. The thrombolytic activity induced by PAK01 was confirmed in murine in situ thromboembolic stroke model where mice were anesthetized before thrombin is injected into middle cerebral artery to produce the clot formation (as described by Orset et al.). To induce reperfusion, PAK01 (7.5 mg/kg) or t-PA (10 mg/kg) was administered intravenously 20 minutes after thrombin injection. The results showed that both PAK01 and t-PA promote reperfusion in mice with middle cerebral artery in situ thromboembolic occlusion. Furthermore, PAK01 yields better treatment results in reducing infarct volume and neurological deficit with lower risk of hemorrhagic transformation when compared to that of t-PA. In addition, rattus carotid artery thrombosis model where 1.4 mg/kg of PAK01 was intravenously administered 4, 6, and 24 hours after stroke onset showed improvements in neuronal behavior outcome and reductions of brain infarct size. In contrast to 3 mg/kg of t-PA, no bleeding was observed even in 7 mg/kg of PAK01-treated animals. HPLC-FT/MS monitoring indicated that PAK01 can cross blood cerebral barrier. A distinct action mechanism out of plasminogen pathway was also explored. In conclusion, based on a new action mechanism the treatment potential of PAK01, a small molecule, in acute ischemic stroke through enhancing reperfusion and neuroprotection, as well as avoiding hemorrhagic transformation was demonstrated in in vivo studies.
Author Disclosures: S. Lin: None. X. Jiang: None. X. Zhang: None. Y. Wang: None. Y. Wang: None. Y. Zhang: None. L. Gui: None. S. Li: None. Y. Wang: None. K. Yao: None. J. Wu: None. M. Zhao: None. S. Peng: None.
- © 2014 by American Heart Association, Inc.