Neurochemical Research

, Volume 34, Issue 3, pp 566–573 | Cite as

Blood–Brain Barrier Efflux Transport of Pyrimidine Nucleosides and Nucleobases in the Rat

  • Zoran B. Redzic
  • Slava A. Malatiali
  • James D. Craik
  • Miodrag L. Rakic
  • Aleksandra J. Isakovic
Original Paper

Abstract

The brain efflux index (BEI), a measurement of blood–brain barrier (BBB) efflux transport, was estimated at 15 s, 30 s, 1 min, 3 min and 10 min after intracerebral injection of [14C]pyrimidines. An initial steep increase of the BEI values over time was observed for [14]uracil and [14C]thymine, followed by a more moderate increase after 1 min. For the corresponding nucleosides, [14C]uridine and [14C]thymidine, the increase of BEI values over time was less steep and linear between 30 s and 3 min. The apparent BBB efflux clearances for [14C]uridine, [14C]thymidine, [14C]uracil and [14C]thymine were (μl/min/g): 95.2 ± 12.1, 125.3 ± 18.4, 290.4 ± 28 and 358.5 ± 32.5, respectively, which is at least several folds higher than the predicted BBB influx clearances of uridine, uracil and thymidine. Quick depletion of brain parenchyma from brain microvasculature has revealed that [14C] radioactivity accumulated in brain microvessels after injection of nucleosides [14C]thymidine and [14C]uridine, but that was not observed when nucleobases, [14C]thymine and [14C]uracil, were injected. Reverse transcriptase-PCR revealed that the rat brain and liver (positive control) express dihydropyrimidine dehydrogenase, a key enzyme in pyrimidine nucleobase catabolism. Two bands representing spliced variants have been detected with the relative density of the bands (expressed relative to the density of glyceraldehyde3-phosphate dehydrogenase bands, mean ± SEM from 3 separate samples) 0.16 ± 0.06 and 0.04 ± 0.01 (brain) and 0.49 ± 0.1 and 0.07 ± 0.01 (liver). Overall, these results indicate that the net direction of pyrimidine BBB transport is the efflux transport; rapid BBB efflux transport and metabolic breakdown of pyrimidine nucleobases appear to be important for brain homeostasis.

Keywords

Brain efflux index Brain efflux clearance Pyrimidines Dihydropyrimidine dehydrogenase Uridine Thymidine 

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Zoran B. Redzic
    • 1
  • Slava A. Malatiali
    • 1
  • James D. Craik
    • 2
  • Miodrag L. Rakic
    • 3
  • Aleksandra J. Isakovic
    • 4
  1. 1.Department of Physiology, Faculty of MedicineKuwait UniversitySafatKuwait
  2. 2.Department of Biochemistry, Faculty of MedicineKuwait UniversitySafatKuwait
  3. 3.Department of NeurosurgerySchool of MedicineBelgradeSerbia
  4. 4.Department of BiochemistrySchool of MedicineBelgradeSerbia

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