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Pharm Res. 2017 Dec;34(12):2652-2662. doi: 10.1007/s11095-017-2263-7. Epub 2017 Sep 26.

Disease-Induced Alterations in Brain Drug Transporters in Animal Models of Alzheimer's Disease : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla.

Author information

1
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, FI, Finland. Kati-Sisko.Vellonen@uef.fi.
2
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, FI, Finland.
3
Laboratoire de la barrière hémato-encéphalique (LBHE), University Artois, Lens, France.
4
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
5
QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.

Abstract

PURPOSE:

Alzheimer's disease (AD) may disturb functions of the blood-brain barrier and change the disposition of drugs to the brain. This study assessed the disease-induced changes in drug transporters in the brain capillaries of transgenic AD mice.

METHODS:

Eighteen drug transporters and four tight junction-associated proteins were analyzed by RT-qPCR in cortex, hippocampus and cerebellum tissue samples of 12-16-month-old APdE9, Tg2576 and APP/PS1 transgenic mice and their healthy age-matched controls. In addition, microvessel fractions enriched from 1-3-month-old APdE9 mice were analyzed using RT-qPCR and Western blotting. Brain transport of methotrexate in APdE9 mice was assessed by in vivo microdialysis.

RESULTS:

The expression profiles of studied genes were similar in brain tissues of AD and control mice. Instead, in the microvessel fraction in APdE9 mice, >2-fold alterations were detected in the expressions of 11 genes but none at the protein level. In control mice strains, >5-fold changes between different brain regions were identified for Slc15a2, Slc22a3 and occludin. Methotrexate distribution into hippocampus of APdE9 mice was faster than in controls.

CONCLUSIONS:

The expression profile of mice carrying presenilin and amyloid precursor protein mutations is comparable to controls, but clear regional differences exist in the expression of drug transporters in brain.

KEYWORDS:

APdE9; CNS exposure; blood-brain barrier; brain disposition; brain microdialysis; pharmacokinetics

PMID:
28952054
DOI:
10.1007/s11095-017-2263-7
[Indexed for MEDLINE]

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