期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 11, 期 3, 页码 539-546出版社
WILEY
DOI: 10.1111/jth.12128
关键词
neurotoxicity; thrombolytic; tissue-type plasminogen activator
资金
- Institut National de la Sante Et de la Recherche Medicale
- French Ministry of Research and Technology
- Eurostroke-Arise Program [FP7/2007-2013-201024]
Background Thrombolysis with tissue-type plasminogen activator (t-PA) is the only treatment approved for acute ischemic stroke. Although t-PA is an efficient clot lysis enzyme, it also causes damage to the neurovascular unit, including hemorrhagic transformations and neurotoxicity. Objectives On the basis of the mechanism of action of t-PA on neurotoxicity, we aimed at studying the molecular requirements to generate safer thrombolytics. Methods We produced original t-PA-related mutants, including a non-cleavable single-chain form with restored zymogenicity (sc*-t-PA) and a t-PA modified in the kringle2 lysine-binding site (K2*-t-PA). Both sc*-t-PA and K2*-t-PA showed fibrinolytic activities similar to that of wild-type t-PA on both euglobulin-containing and plasma-containing clots. In contrast to wild-type t-PA, the two mutants did not promote N-methyl-d-aspartate receptor-mediated neurotoxicity. Conclusions We designed t-PA mutants with molecular properties that, in contrast to t-PA, do not induce neurotoxicity.
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