Altered brain uptake of therapeutics in a triple transgenic mouse model of Alzheimer's disease.
Pharm Res
; 30(11): 2868-79, 2013 Nov.
Article
em En
| MEDLINE
| ID: mdl-23794039
ABSTRACT
PURPOSE:
The purpose of this study was to systematically assess the impact of Alzheimer's disease (AD)-associated blood-brain barrier (BBB) alterations on the uptake of therapeutics into the brain.METHODS:
The brain uptake of probe compounds was measured in 18-20 month old wild type (WT) and triple transgenic (3×TG) AD mice using an in situ transcardiac perfusion technique. These results were mechanistically correlated with immunohistochemical and molecular studies.RESULTS:
The brain uptake of the paracellular marker, [(14)C] sucrose, did not differ between WT and 3×TG mice. The brain uptake of passively diffusing markers, [(3)H] diazepam and [(3)H] propranolol, decreased 54-60% in 3×TG mice, consistent with a 33.5% increase in the thickness of the cerebrovascular basement membrane in 3×TG mice. Despite a 42.4% reduction in P-gp expression in isolated brain microvessels from a sub-population of 3×TG mice (relative to WT mice), the brain uptake of P-gp substrates ([(3)H] digoxin, [(3)H] loperamide and [(3)H] verapamil) was not different between genotypes, likely due to a compensatory thickening in the cerebrovascular basement membrane counteracting any reduced efflux of these lipophilic substrates.CONCLUSION:
These studies systematically assessed the impact of AD on BBB drug transport in a relevant animal model, and have demonstrated a reduction in the brain uptake of passively-absorbed molecules in this mouse model of AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
/
Farmacocinética
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Doença de Alzheimer
Limite:
Animals
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Humans
Idioma:
En
Revista:
Pharm Res
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Austrália