Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke
Background Thrombolysis and endovascular thrombectomy are the primary treatment for ischemic stroke. However, due to the limited time window and the occurrence of adverse effects, only a small number of patients can genuinely benefit from recanalization. Intraarterial injection of rtPA (recombinant...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.123.029817 |
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| author | Yuyou Huang Shanshan Gu Ziping Han Zhenghong Yang Liyuan Zhong Lingzi Li Rongliang Wang Feng Yan Yumin Luo Cesario Borlongan Jie Lu |
| author_facet | Yuyou Huang Shanshan Gu Ziping Han Zhenghong Yang Liyuan Zhong Lingzi Li Rongliang Wang Feng Yan Yumin Luo Cesario Borlongan Jie Lu |
| author_sort | Yuyou Huang |
| collection | DOAJ |
| description | Background Thrombolysis and endovascular thrombectomy are the primary treatment for ischemic stroke. However, due to the limited time window and the occurrence of adverse effects, only a small number of patients can genuinely benefit from recanalization. Intraarterial injection of rtPA (recombinant tissue plasminogen activator) based on arterial thrombectomy could improve the prognosis of patients with acute ischemic stroke, but it could not reduce the incidence of recanalization‐related adverse effects. Recently, selective brain hypothermia has been shown to offer neuroprotection against stroke. To enhance the recanalization rate of ischemic stroke and reduce the adverse effects such as tiny thrombosis, brain edema, and hemorrhage, we described for the first time a combined approach of hypothermia and thrombolysis via intraarterial hypothermic rtPA. Methods and Results We initially established the optimal regimen of hypothermic rtPA in adult rats subjected to middle cerebral artery occlusion. Subsequently, we explored the mechanism of action mediating hypothermic rtPA by probing reduction of brain tissue temperature, attenuation of blood–brain barrier damage, and sequestration of inflammation coupled with untargeted metabolomics. Hypothermic rtPA improved neurological scores and reduced infarct volume, while limiting hemorrhagic transformation in middle cerebral artery occlusion rats. These therapeutic outcomes of hypothermic rtPA were accompanied by reduced brain temperature, glucose metabolism, and blood–brain barrier damage. A unique metabolomic profile emerged in hypothermic rtPA‐treated middle cerebral artery occlusion rats characterized by downregulated markers for energy metabolism and inflammation. Conclusions The innovative use of hypothermic rtPA enhances their combined, as opposed to stand‐alone, neuroprotective effects, while reducing hemorrhagic transformation in ischemic stroke. |
| first_indexed | 2024-03-12T01:51:07Z |
| format | Article |
| id | doaj.art-3d58990269d04a378593a5f3aaf45ee1 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-12T01:51:07Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-3d58990269d04a378593a5f3aaf45ee12023-09-08T12:39:35ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802023-09-01121710.1161/JAHA.123.029817Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental StrokeYuyou Huang0Shanshan Gu1Ziping Han2Zhenghong Yang3Liyuan Zhong4Lingzi Li5Rongliang Wang6Feng Yan7Yumin Luo8Cesario Borlongan9Jie Lu10Department of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaDepartment of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaDepartment of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaDepartment of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaDepartment of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaDepartment of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaDepartment of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaDepartment of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaDepartment of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaUniversity of South Florida Tampa FLDepartment of Radiology and Nuclear Medicine, Institute of Cerebrovascular Diseases Research Xuanwu Hospital of Capital Medical University Beijing ChinaBackground Thrombolysis and endovascular thrombectomy are the primary treatment for ischemic stroke. However, due to the limited time window and the occurrence of adverse effects, only a small number of patients can genuinely benefit from recanalization. Intraarterial injection of rtPA (recombinant tissue plasminogen activator) based on arterial thrombectomy could improve the prognosis of patients with acute ischemic stroke, but it could not reduce the incidence of recanalization‐related adverse effects. Recently, selective brain hypothermia has been shown to offer neuroprotection against stroke. To enhance the recanalization rate of ischemic stroke and reduce the adverse effects such as tiny thrombosis, brain edema, and hemorrhage, we described for the first time a combined approach of hypothermia and thrombolysis via intraarterial hypothermic rtPA. Methods and Results We initially established the optimal regimen of hypothermic rtPA in adult rats subjected to middle cerebral artery occlusion. Subsequently, we explored the mechanism of action mediating hypothermic rtPA by probing reduction of brain tissue temperature, attenuation of blood–brain barrier damage, and sequestration of inflammation coupled with untargeted metabolomics. Hypothermic rtPA improved neurological scores and reduced infarct volume, while limiting hemorrhagic transformation in middle cerebral artery occlusion rats. These therapeutic outcomes of hypothermic rtPA were accompanied by reduced brain temperature, glucose metabolism, and blood–brain barrier damage. A unique metabolomic profile emerged in hypothermic rtPA‐treated middle cerebral artery occlusion rats characterized by downregulated markers for energy metabolism and inflammation. Conclusions The innovative use of hypothermic rtPA enhances their combined, as opposed to stand‐alone, neuroprotective effects, while reducing hemorrhagic transformation in ischemic stroke.https://www.ahajournals.org/doi/10.1161/JAHA.123.029817blood–brain barrierhypothermiainflammationischemic strokemiddle cerebral artery occlusiontissue plasminogen activator |
| spellingShingle | Yuyou Huang Shanshan Gu Ziping Han Zhenghong Yang Liyuan Zhong Lingzi Li Rongliang Wang Feng Yan Yumin Luo Cesario Borlongan Jie Lu Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease blood–brain barrier hypothermia inflammation ischemic stroke middle cerebral artery occlusion tissue plasminogen activator |
| title | Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke |
| title_full | Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke |
| title_fullStr | Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke |
| title_full_unstemmed | Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke |
| title_short | Cold Case of Thrombolysis: Cold Recombinant Tissue Plasminogen Activator Confers Enhanced Neuroprotection in Experimental Stroke |
| title_sort | cold case of thrombolysis cold recombinant tissue plasminogen activator confers enhanced neuroprotection in experimental stroke |
| topic | blood–brain barrier hypothermia inflammation ischemic stroke middle cerebral artery occlusion tissue plasminogen activator |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.123.029817 |
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