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

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

doi:10.3390/ijms23031403

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.

Highlights

Cerebral stroke is the second leading cause of death worldwide, with ischemic stroke accounting for 87% of all cases
In view of the finding that vascular bleeding after delayed Recombinant tissue plasminogen activator (rtPA) treatment is closely associated with matrix metalloproteinase (MMP) activation [1,15], we focused on ascertaining whether MMPrelated mechanisms are involved in inhibition of rtPA-induced hemorrhagic complications by otaplimastat
Treatment with rtPA at 6 h after embolism induced a significant increase in cerebral hemorrhagic transformation, which was completely suppressed by otaplimastat (Figure 1e)

Summary

Introduction

Cerebral stroke is the second leading cause of death worldwide, with ischemic stroke accounting for 87% of all cases. Over the past 30 years, all attempts to develop effective cytoprotective agents for cerebral ischemic stroke treatment have failed. The majority of currently available agents present single targets against excitotoxicity, oxidative stress or inflammatory responses occurring during ischemia-reperfusion. Therapeutic failure is potentially attributable to damage or death of brain cells through diverse pathways after ischemia. Recombinant tissue plasminogen activator (rtPA) is the only agent approved by FDA for patients with acute ischemic stroke. The delayed treatment of rtPA might be associated with hemorrhagic transformation and mortality [2,3,4] and has various neurodegenerative effects, including modulation of neuronal excitotoxicity and inflammatory responses [3]. Only a few patients receive (3~8.5%) and benefit (1~2%) from tPA treatment [5]

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Results

Conclusion