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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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Autores principales: Song, Hwa Young, Chung, Jee-In, Jalin, Angela Melinda Anthony, Ju, Chung, Pahk, Kisoo, Joung, Chanmin, Lee, Sekwang, Jin, Sejong, Kim, Byoung Soo, Lee, Ki Sung, Ryu, Jei-Man, Kim, Won-Ki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835804/
https://www.ncbi.nlm.nih.gov/pubmed/35163322
http://dx.doi.org/10.3390/ijms23031403
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author Song, Hwa Young
Chung, Jee-In
Jalin, Angela Melinda Anthony
Ju, Chung
Pahk, Kisoo
Joung, Chanmin
Lee, Sekwang
Jin, Sejong
Kim, Byoung Soo
Lee, Ki Sung
Ryu, Jei-Man
Kim, Won-Ki
author_facet Song, Hwa Young
Chung, Jee-In
Jalin, Angela Melinda Anthony
Ju, Chung
Pahk, Kisoo
Joung, Chanmin
Lee, Sekwang
Jin, Sejong
Kim, Byoung Soo
Lee, Ki Sung
Ryu, Jei-Man
Kim, Won-Ki
author_sort Song, Hwa Young
collection PubMed
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.
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spelling pubmed-88358042022-02-12 The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia Song, Hwa Young Chung, Jee-In Jalin, Angela Melinda Anthony Ju, Chung Pahk, Kisoo Joung, Chanmin Lee, Sekwang Jin, Sejong Kim, Byoung Soo Lee, Ki Sung Ryu, Jei-Man Kim, Won-Ki Int J Mol Sci Article 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. MDPI 2022-01-26 /pmc/articles/PMC8835804/ /pubmed/35163322 http://dx.doi.org/10.3390/ijms23031403 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Song, Hwa Young
Chung, Jee-In
Jalin, Angela Melinda Anthony
Ju, Chung
Pahk, Kisoo
Joung, Chanmin
Lee, Sekwang
Jin, Sejong
Kim, Byoung Soo
Lee, Ki Sung
Ryu, Jei-Man
Kim, Won-Ki
The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835804/
https://www.ncbi.nlm.nih.gov/pubmed/35163322
http://dx.doi.org/10.3390/ijms23031403
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