The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia
Acute ischemic stroke is the leading cause of morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only agent clinically approved by FDA for patients with acute ischemic stroke. However, delayed treatment of rtPA (e.g., more than 3 h after stroke onset) exacerbat...
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/3/1403 |
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| author | Hwa Young Song Jee-In Chung Angela Melinda Anthony Jalin Chung Ju Kisoo Pahk Chanmin Joung Sekwang Lee Sejong Jin Byoung Soo Kim Ki Sung Lee Jei-Man Ryu Won-Ki Kim |
| author_facet | Hwa Young Song Jee-In Chung Angela Melinda Anthony Jalin Chung Ju Kisoo Pahk Chanmin Joung Sekwang Lee Sejong Jin Byoung Soo Kim Ki Sung Lee Jei-Man Ryu Won-Ki Kim |
| author_sort | Hwa Young Song |
| collection | DOAJ |
| description | Acute ischemic stroke is the leading cause of morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only agent clinically approved by FDA for patients with acute ischemic stroke. However, delayed treatment of rtPA (e.g., more than 3 h after stroke onset) exacerbates ischemic brain damage by causing intracerebral hemorrhage and increasing neurotoxicity. In the present study, we investigated whether the neuroprotant otaplimastat reduced delayed rtPA treatment-evoked neurotoxicity in male Sprague Dawley rats subjected to embolic middle cerebral artery occlusion (eMCAO). Otaplimastat reduced cerebral infarct size and edema and improved neurobehavioral deficits. In particular, otaplimastat markedly reduced intracerebral hemorrhagic transformation and mortality triggered by delayed rtPA treatment, consequently extending the therapeutic time window of rtPA. We further found that ischemia-evoked extracellular matrix metalloproteases (MMPs) expression was closely correlated with cerebral hemorrhagic transformation and brain damage. In ischemic conditions, delayed rtPA treatment further increased brain injury via synergistic expression of MMPs in vascular endothelial cells. In oxygen-glucose-deprived endothelial cells, otaplimastat suppressed the activity rather than protein expression of MMPs by restoring the level of tissue inhibitor of metalloproteinase (TIMP) suppressed in ischemia, and consequently reduced vascular permeation. This paper shows that otaplimastat under clinical trials is a new drug which can inhibit stroke on its own and extend the therapeutic time window of rtPA, especially when administered in combination with rtPA. |
| first_indexed | 2024-03-09T23:47:56Z |
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| last_indexed | 2024-03-09T23:47:56Z |
| publishDate | 2022-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9c15cd6034c14f6e844b9eba7020c66c2023-11-23T16:39:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233140310.3390/ijms23031403The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral IschemiaHwa Young Song0Jee-In Chung1Angela Melinda Anthony Jalin2Chung Ju3Kisoo Pahk4Chanmin Joung5Sekwang Lee6Sejong Jin7Byoung Soo Kim8Ki Sung Lee9Jei-Man Ryu10Won-Ki Kim11Department of Neuroscience, Korea University College of Medicine, Seoul 02841, KoreaDepartment of Neuroscience, Korea University College of Medicine, Seoul 02841, KoreaDepartment of Neuroscience, Korea University College of Medicine, Seoul 02841, KoreaDepartment of Neuroscience, Korea University College of Medicine, Seoul 02841, KoreaDepartment of Neuroscience, Korea University College of Medicine, Seoul 02841, KoreaDepartment of Neuroscience, Korea University College of Medicine, Seoul 02841, KoreaDepartment of Neuroscience, Korea University College of Medicine, Seoul 02841, KoreaDepartment of Neuroscience, Korea University College of Medicine, Seoul 02841, KoreaResearch Headquarters, Shin Poong Pharm. Co., Ltd., Ansan 15610, KoreaResearch Headquarters, Shin Poong Pharm. Co., Ltd., Ansan 15610, KoreaResearch Headquarters, Shin Poong Pharm. Co., Ltd., Ansan 15610, KoreaDepartment of Neuroscience, Korea University College of Medicine, Seoul 02841, KoreaAcute ischemic stroke is the leading cause of morbidity and mortality worldwide. Recombinant tissue plasminogen activator (rtPA) is the only agent clinically approved by FDA for patients with acute ischemic stroke. However, delayed treatment of rtPA (e.g., more than 3 h after stroke onset) exacerbates ischemic brain damage by causing intracerebral hemorrhage and increasing neurotoxicity. In the present study, we investigated whether the neuroprotant otaplimastat reduced delayed rtPA treatment-evoked neurotoxicity in male Sprague Dawley rats subjected to embolic middle cerebral artery occlusion (eMCAO). Otaplimastat reduced cerebral infarct size and edema and improved neurobehavioral deficits. In particular, otaplimastat markedly reduced intracerebral hemorrhagic transformation and mortality triggered by delayed rtPA treatment, consequently extending the therapeutic time window of rtPA. We further found that ischemia-evoked extracellular matrix metalloproteases (MMPs) expression was closely correlated with cerebral hemorrhagic transformation and brain damage. In ischemic conditions, delayed rtPA treatment further increased brain injury via synergistic expression of MMPs in vascular endothelial cells. In oxygen-glucose-deprived endothelial cells, otaplimastat suppressed the activity rather than protein expression of MMPs by restoring the level of tissue inhibitor of metalloproteinase (TIMP) suppressed in ischemia, and consequently reduced vascular permeation. This paper shows that otaplimastat under clinical trials is a new drug which can inhibit stroke on its own and extend the therapeutic time window of rtPA, especially when administered in combination with rtPA.https://www.mdpi.com/1422-0067/23/3/1403otaplimastatembolic middle cerebral artery occlusionhemorrhagerecombinant tissue plasminogen activatormatrix metalloproteasetissue inhibitor matrix metalloproteinase |
| spellingShingle | Hwa Young Song Jee-In Chung Angela Melinda Anthony Jalin Chung Ju Kisoo Pahk Chanmin Joung Sekwang Lee Sejong Jin Byoung Soo Kim Ki Sung Lee Jei-Man Ryu Won-Ki Kim The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia International Journal of Molecular Sciences otaplimastat embolic middle cerebral artery occlusion hemorrhage recombinant tissue plasminogen activator matrix metalloprotease tissue inhibitor matrix metalloproteinase |
| title | The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia |
| title_full | The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia |
| title_fullStr | The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia |
| title_full_unstemmed | The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia |
| title_short | The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia |
| title_sort | quinazoline otaplimastat sp 8203 reduces the hemorrhagic transformation and mortality aggravated after delayed rtpa induced thrombolysis in cerebral ischemia |
| topic | otaplimastat embolic middle cerebral artery occlusion hemorrhage recombinant tissue plasminogen activator matrix metalloprotease tissue inhibitor matrix metalloproteinase |
| url | https://www.mdpi.com/1422-0067/23/3/1403 |
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