The Quinazoline Otaplimastat (SP-8203) Reduces the Hemorrhagic Transformation and Mortality Aggravated after Delayed rtPA-Induced Thrombolysis in Cerebral Ischemia.
Hwa Young SongJee-In ChungAngela Melinda Anthony JalinChung JuKisoo PahkChanmin JoungSekwang LeeSejong JinByoung Soo KimKi Sung LeeJei-Man RyuWon-Ki KimPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- cerebral ischemia
- brain injury
- acute ischemic stroke
- subarachnoid hemorrhage
- endothelial cells
- clinical trial
- middle cerebral artery
- extracellular matrix
- high glucose
- emergency department
- heart failure
- randomized controlled trial
- traumatic brain injury
- combination therapy
- cardiovascular events
- type diabetes
- functional connectivity
- mass spectrometry
- skeletal muscle
- high resolution
- ischemia reperfusion injury
- cardiovascular disease
- coronary artery disease
- resting state
- vascular endothelial growth factor
- binding protein
- electronic health record
- cancer therapy
- internal carotid artery
- percutaneous coronary intervention
- atomic force microscopy
- open label
- cell free
- cerebral blood flow