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Decreased blood-brain barrier P-glycoprotein function with aging

Introduction

P-glycoprotein (P-gp) acts at the blood-brain barrier (BBB) as an active cell membrane efflux pump for several endogenous and exogenous compounds. The P-gp substrate (R)-[11C]verapamil (VPM) can be used to measure P-gp-mediated transport at the BBB in vivo with positron emission tomography (PET). The distribution volume (DV) of VPM has been shown to inversely reflect P-gp function in the BBB [1].

Materials and methods

A young (n = 7, mean age: 28.0 ± 3.8 years) and an aged group (n = 6, mean age: 69.4 ± 8.5 years) of healthy volunteers underwent dynamic VPM PET scans and arterial blood sampling. Radiolabelled metabolites of VPM were quantified by a previously described combined solid-phase extraction/HPLC protocol [1]. A whole-brain grey matter region was defined by using the Hammersmith n20r49 brain atlas [2]. The DV of VPM was estimated by using a 2-rate-constant-1-tissue-compartment model [1].

Results

Mean DV s (± standard deviation) of VPM were 0.50 ± 0.08 for the young and 0.63 ± 0.13 for the aged group (+27% for the aged group, p = 0.04, 2-tailed t-test). There was no significant difference in VPM metabolism between the young and the aged group (area under the curve of the fraction of polar [11C]metabolites of VPM versus time in arterial plasma: 12.7 ± 2.4 and 14.1 ± 3.6 for the young and the aged group, respectively, p = 0.19, 2-tailed t-test).

Conclusion

Our data confirm previous results that older subjects show significantly decreased P-gp function in the BBB [1, 3]. Decreased P-gp function can lead to increased accumulation of toxins and drugs in the aging brain and could thus be a risk factor for the development of neurodegenerative disease.

References

  1. Toornvliet R, van Berckel BN, Luurtsema G, Lubberink M, Geldof AA, Bosch TM, Oerlemans R, Lammertsma AA, Franssen EJ: Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[11C]verapamil and positron emission tomography. Clin Pharmacol Ther. 2006, 79: 540-548. 10.1016/j.clpt.2006.02.004.

    Article  CAS  PubMed  Google Scholar 

  2. Hammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, Mitchell TN, Brooks DJ, Duncan JS: Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003, 19: 224-247. 10.1002/hbm.10123.

    Article  PubMed  Google Scholar 

  3. Bartels AL, Kortekaas R, Bart J, Willemsen AT, de Klerk OL, de Vries JJ, van Oostrom JC, Leenders KL: Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: A possible role in progressive neurodegeneration. Neurobiol Aging.

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Correspondence to Oliver Langer.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Bauer, M., Karch, R., Abrahim, A. et al. Decreased blood-brain barrier P-glycoprotein function with aging. BMC Pharmacol 8 (Suppl 1), A48 (2008). https://doi.org/10.1186/1471-2210-8-S1-A48

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  • DOI: https://doi.org/10.1186/1471-2210-8-S1-A48

Keywords

  • Positron Emission Tomography
  • Verapamil
  • Distribution Volume
  • Aged Group
  • Positron Emission Tomography Scan