In:
Journal of Cerebral Blood Flow & Metabolism, SAGE Publications, Vol. 29, No. 1 ( 2009-01), p. 25-33
Abstract:
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 125 I-labeled plasma-derived mouse APC enters the brain from cerebrovascular circulation by a concentration-dependent mechanism. The permeability surface area product of 125 I-APC (0.1 nmol/L) in different forebrain regions ranged from 3.11 to 4.13 μL/min/g brain. This was approximately 80- to 110-fold greater than for 14 C-inulin, a simultaneously infused reference tracer. The K m 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.
Type of Medium:
Online Resource
ISSN:
0271-678X
,
1559-7016
DOI:
10.1038/jcbfm.2008.117
Language:
English
Publisher:
SAGE Publications
Publication Date:
2009
detail.hit.zdb_id:
2039456-1
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