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2016 Scientific Sessions Sol Sherry Distinguished Lecturer in Thrombosis:
Thrombotic Stroke: Neuroprotective Therapy by Recombinant-Activated Protein C
#MMPMID27758767
Griffin JH
; Mosnier LO
; Fernández JA
; Zlokovic BV
Arterioscler Thromb Vasc Biol
2016[Nov]; 36
(11
): 2143-2151
PMID27758767
show ga
APC (activated protein C), derived from the plasma protease zymogen, is
antithrombotic and anti-inflammatory. In preclinical injury models, recombinant
APC provides neuroprotection for multiple injuries, including ischemic stroke.
APC acts directly on brain endothelial cells and neurons by initiating cell
signaling that requires multiple receptors. Two or more major APC receptors
mediate APC's neuroprotective cell signaling. When bound to endothelial cell
protein C receptor, APC can cleave protease-activated receptor 1, causing biased
cytoprotective signaling that reduces ischemia-induced injury. Pharmacological
APC alleviates bleeding induced by tissue-type plasminogen activator in murine
ischemic stroke studies. Remarkably, APC's signaling promotes neurogenesis. The
signaling-selective recombinant variant of APC, 3K3A-APC, was engineered to lack
most of the APC's anticoagulant activity but retain APC's cell signaling actions.
Recombinant 3K3A-APC is in ongoing National Institutes of Health (NIH)-funded
clinical trials for ischemic stroke.
free
free
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