Abstract 129: PAK01: A Synthesized Small Molecule That Enhances Reperfusion, Neuroprotection and Avoids Hemorrhagic Transformation in Rodent Models of Thromboembolic Stroke
Shinn‐Zong LinXueyun JiangXiaoyi ZhangYuji WangYaonan WangYingjie ZhangLin GuiShan LiYanming WangKun YaoJianhui WuMing ZhaoShiqi Peng
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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.Keywords:
Stroke
Thromboembolic stroke
Neurotoxicity
Free radical scavenger
Free radical scavenger
Microdialysis
Rose bengal
Scavenger
Hydroxyl radical
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Edaravone
Free radical scavenger
Scavenger
Stroke
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Background and hypothesis Functional improvement after middle cerebral artery ischaemia seems to depend on recanalization of large-vessel occlusion as early as possible. The only approved medical treatment for acute stroke is early IV tissue plasminogen activator administration. However, while some patients do not benefit from quick recanalization, others recover despite persistent middle cerebral artery occlusion. We wondered whether there are different effects of tissue plasminogen activator treatment on large artery and small artery reopening. Methods We enrolled 55 acute stroke patients who showed persisting middle cerebral artery occlusion evidenced by transcranial colour-coded duplex ultrasonography in follow-up examination within 48 h postonset of middle cerebral artery stroke syndromes (mean 30·8 ± 5·4 h after admission). Twenty-two of 55 had been treated with tissue plasminogen activator and 33/55 had been treated without tissue plasminogen activator. We compared neurological (National Institutes of Health Stroke Scale) and functional (modified Rankin Scale) scores at baseline, after seven-days, and then after two-months. Risk factors, previous stroke prophylaxis, as well as clinical baseline characteristics were analysed to exclude significant differences between both groups. Results Despite later admission to hospital (tissue plasminogen activator patients 1·6 ± 0·66 h vs. non-tissue plasminogen activator patients 7·4 ± 5·84 h; P < 0·001), there was no significant difference between both groups concerning demographic data, severity of symptoms on admission, risk factors, stroke prophylaxis, as well as basic laboratory values (international normalized ratio, leucocyte count, C-reactive protein) blood pressure and body temperature on admission. Irrespective of Doppler findings demonstrating persistent middle cerebral artery occlusion in all 55 patients, there was a significant neurological and functional improvement in tissue plasminogen activator patients compared to non-tissue plasminogen activator patients. Tissue plasminogen activator patients had a mean improvement on National Institutes of Health Stroke Scale within the first seven-days of 2·8 points, while non-tissue plasminogen activator patients deteriorated by 2·2 points ( P < 0·001). Concerning modified Rankin Scale tissue plasminogen activator-treated patients showed a mean improvement within the first seven-days of 0·5 points, while non-tissue plasminogen activator patients deteriorated by 0·3 points ( P = 0·019). A favourable overall short-term clinical course (i.e. improvement on National Institutes of Health Stroke Scale >3 points and/or modified Rankin Scale >1 point) was found in 36·4% of tissue plasminogen activator patients and in 6·1% of non-tissue plasminogen activator patients ( P = 0·0047). At two-months follow-up, patients still showed a median modified Rankin Scale of 4 points after tissue plasminogen activator treatment and 5 points after non-tissue plasminogen activator treatment ( P = 0·023). Conclusion Although the prognosis of patients with persisting middle cerebral artery occlusion after tissue plasminogen activator administration is known to be poor, patients do better if treated with tissue plasminogen activator vs. those who could not be treated – mainly for late presentation. This may be due to sufficient small vascular territory recanalization despite persistence of large artery occlusion after tissue plasminogen activator treatment.
Stroke
T-plasminogen activator
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Edaravone
Free radical scavenger
Scavenger
Brain tissue
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In acute ischemic stroke patients, administration of tissue plasminogen activator (tPA) was proven to improve clinical outcome. On the other hand, neurotoxic effects of tPA have been reported in animal experimental studies. Using a rat thromboembolic stroke model, we examined whether or not the free radical scavenger, edaravone, could attenuate such neurotoxic effect of tPA administered for the purpose of fibrinolysis. Even when early recanalization was induced by administering tPA at 30 minutes after the onset of ischemia, significant amount of tPA was extravasated through the cerebral vessels. Edaravone significantly attenuated extravasation of tPA. Combination therapy using tPA and edaravone appears to be a promising strategy for diminishing the negative effects of tPA.
Edaravone
Free radical scavenger
Extravasation
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In recent years, evidence has been accumulating that tissue plasminogen activator (tPA) possesses neurotoxic effects. However, such deleterious effects have been attributed to endogenously generated tPA. In the present study, focusing on exogenously administered tPA for the purpose of fibrinolysis, we evaluated the extent and the degree of extravasated tPA in a rat model of thromboembolic stroke. Even after early recanalization of occluded cerebral vessels, significant infiltration of tPA occurred through the cerebral vessels. It is assumed that exogenous tPA also exerts neurotoxic effects in the ischemic brain tissue.
Infiltration (HVAC)
Thromboembolic stroke
Brain tissue
Stroke
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Extravasation
Thromboembolic stroke
Stroke
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Edaravone
Free radical scavenger
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Supine position
External carotid artery
Superficial temporal artery
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Deleterious effects of tissue plasminogen activator (tPA) have been described recently in experimental studies. For example, tPA can aggravate ischemic neuronal damage through its proteolytic activity. The present study was undertaken to examine whether or not the free radical scavenger, edaravone, could prevent the extravasation of tPA administered for the purpose of fibrinolysis in a rat model of thromboembolic stroke.Significant amounts of tPA were extravasated through the cerebral vessels even when early recanalization was induced by administering tPA at 30 minutes after the onset of schema. Edaravone significantly attenuated such extravasation of tPA.In acute ischemic stroke patients, combination therapy using tPA with edaravone appears to be a reasonable strategy for diminishing the negative effects of tPA.
Edaravone
Extravasation
Free radical scavenger
Thromboembolic stroke
Fibrinolytic agent
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