Document Detail

A narrow time-window for access to the brain by exogenous protein after immunological targeting of a blood-brain barrier antigen.
MedLine Citation:
PMID:  15144799     Owner:  NLM     Status:  MEDLINE    
The endothelial barrier antigen (EBA) is a membrane protein expressed by endothelial cells of the rat blood-brain barrier (BBB). A previous short-term non-recovery study demonstrated that immunological targeting of EBA by intravenous administration of a monoclonal antibody (anti-EBA) led to acute opening of the BBB to exogenous and endogenous tracers. The aims of the present study were to determine whether opening of the BBB was reversible and compatible with survival, and whether a "therapeutic window" existed. A single intravenous injection of one of three doses (high, medium and low) of anti-EBA was used. Animals were allowed to survive for periods ranging from 17 min to 4 days. The tracer horseradish peroxidase (HRP) was administered intravenously 10 min before perfusion fixation, and its distribution was assessed in Vibratome sections of the brain and spinal cord. Leakage of HRP into the central nervous system was dose- and time-dependent. The medium dose produced incipient HRP leakage at 17 min and widespread pronounced leakage at 30 min. Progressive reduction in HRP permeability occurred from 45 min to 2 h, with barrier restoration by 3 h. At all subsequent time intervals (6 h-4 days) the BBB remained impermeable to HRP. The low and high doses produced less and greater HRP leakage, respectively, but restoration of the barrier still occurred at 3 h. The high dose, however, produced a number of deaths. Animals treated with an isotype control antibody showed no HRP leakage at comparable time intervals. The results indicated that (1) this model was compatible with survival, (2) opening of the BBB was monophasic and transient, occurring during a narrow "time-window", and (3) the barrier, once reconstituted, maintained its integrity.
M N Ghabriel; J J Lu; R Tadros; G Hermanis
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of comparative pathology     Volume:  131     ISSN:  0021-9975     ISO Abbreviation:  J. Comp. Pathol.     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-05-17     Completed Date:  2004-12-15     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0102444     Medline TA:  J Comp Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  52-60     Citation Subset:  IM    
Department of Anatomical Sciences, University of Adelaide, The Medical School, Frome Road, Adelaide 5005, Australia.
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MeSH Terms
Antibodies, Monoclonal / pharmacology
Antigens, Surface / immunology,  metabolism*
Blood-Brain Barrier / drug effects,  physiology*
Brain / physiology*
Capillary Permeability
Dose-Response Relationship, Drug
Endothelial Cells / metabolism
Horseradish Peroxidase / pharmacokinetics*
Rats, Sprague-Dawley
Spinal Cord / physiology*
Time Factors
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antigens, Surface; 0/endothelial barrier antigen, rat; EC 1.11.1.-/Horseradish Peroxidase

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