The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia

Hwa Young Song, Jee In Chung, A. M. Anthony Jalin, Chung Ju, Kisoo Pahk, Chanmin Joung, Sekwang Lee, Sejong Jin, Byoung Soo Kim, Ki Sung Lee, Jei Man Ryu, Won Ki Kim

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number1403
JournalInternational journal of molecular sciences
Volume23
Issue number3
DOIs
Publication statusPublished - 2022 Feb 1

Bibliographical note

Funding Information:
Funding: This work was supported by a grant from the Korea Health Technology R&D Project (No. HI15C2796) of the Korea Health Industry Development Institute (KHIDI), which is funded by the Ministry of Health and Welfare, republic of Korea.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Embolic middle cerebral artery occlusion
  • Hemorrhage
  • Matrix metalloprotease
  • Otaplimastat
  • Recombinant tissue plasminogen activator
  • Tissue inhibitor matrix metalloproteinase

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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