NEUROPROTECTIVE ACTIVITY OF ACTIVATED PROTEIN C IS INDEPENDENT OF ITS ANTICOAGULANT ACTIVITY

摘要

Activated protein C (APC), prodrug, and/or a variant thereof may be used as aninhibitor of apoptosis or cell death and/or a cell survival factor, especiallyfor stressed or injured cells or tissues of the nervous system includingsubjects with neurodegenerative disorders. Novel biological functions (e.g.,neuroprotection) can be independent or separated from inhibition of clottingor inflammation, and other biological properties of APC (e.g., antithromboticactivity, ability to reduce NFkB-regulated gene expression). It can be used inthe treatment of disease or other pathological conditions by at leastinhibiting the p53-dependent and/or caspase-3-dependent pro-apoptoticsignaling pathways in stressed or injured cells. Thus, APC, prodrugs, andvariants thereof (e.g., APC protease domain mutants with reduced anti-coagulant activity) are prototypes of a class of agents for preventingapoptosis or cell death and/or promoting cell survival by direct action onbrain cells. New protein C and/or APC variants with reduced anticoagulantactivity may be selected thereby.