期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 29, 期 1, 页码 25-33出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2008.117
关键词
activated protein C; APC variants; blood-brain barrier; transport; endothelial protein C receptor
资金
- NIH [HL63290, HL081528, HL073750]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL063290, R01HL081528, P01HL073750] Funding Source: NIH RePORTER
Activated protein C (APC), a serine-protease with anticoagulant, anti-inflammatory, and cytoprotective activities, is neuroprotective and holds potential to treat different neurologic disorders. It is unknown whether APC crosses the blood-brain barrier (BBB) to reach its therapeutic targets in the brain. By using a brain vascular perfusion technique, we show that I-125-labeled plasma-derived mouse APC enters the brain from cerebrovascular circulation by a concentration-dependent mechanism. The permeability surface area product of I-125-APC (0.1 nmol/L) in different forebrain regions ranged from 3.11 to 4.13 mu L/min/g brain. This was approximately 80- to 110-fold greater than for C-14-inulin, a simultaneously infused reference tracer. The Km value for APC BBB cortical transport was 1.6 +/- 0.2 nmol/L. Recombinant APC variants with reduced anticoagulant activity, 5A-APC and 3K3A-APC, but not protein C, exhibited high affinity for the APC BBB transport system. Blockade of APC-binding site on endothelial protein C receptor (EPCR), but not blockade of its protease-activated receptor-1 (PAR1) catalytic site, inhibited by >85% APC entry into the brain. APC brain uptake was reduced by 64% in severely deficient EPCR mice, but not in PAR1 null mice. These data suggest that APC and its variants with reduced anticoagulant activity cross the BBB via EPCR-mediated saturable transport.
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