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

• Published in: International journal of molecular sciences 2022-01, Vol.23 (3), p.1403
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Acetamides; Animals; Brain; Brain damage; Brain injury; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Cerebral blood flow; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - metabolism; Cerebral infarction; Clinical trials; Disease Models, Animal; Edema; embolic middle cerebral artery occlusion; Embolisms; Endothelial cells; Endothelial Cells - metabolism; Extracellular matrix; Fibrinolytic Agents - therapeutic use; Hemorrhage; Humans; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - metabolism; Ischemia; Ischemic Stroke; Male; matrix metalloprotease; Matrix metalloproteinases; Matrix Metalloproteinases - metabolism; Metalloproteinase; Morbidity; Mortality; Neurotoxicity; Occlusion; otaplimastat; Permeability; Proteins; Quinazolines - therapeutic use; Quinazolinones; Rats; Rats, Sprague-Dawley; recombinant tissue plasminogen activator; Stroke; Stroke - metabolism; t-Plasminogen activator; Thrombolysis; Thrombolytic Therapy; tissue inhibitor matrix metalloproteinase; Tissue inhibitor of metalloproteinases; Tissue Plasminogen Activator; Transformations
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031403

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.