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Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain.

Publication ,  Journal Article
Cannon, RE; Peart, JC; Hawkins, BT; Campos, CR; Miller, DS
Published in: Proceedings of the National Academy of Sciences of the United States of America
September 2012

P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. This pathway encompasses elements of proinflammatory- (TNF-α) and sphingolipid-based signaling. Critical to this pathway was signaling through sphingosine-1-phosphate receptor 1 (S1PR1). In brain capillaries, S1P acted through S1PR1 to rapidly and reversibly reduce P-glycoprotein transport activity. Sphingosine reduced transport by a sphingosine kinase-dependent mechanism. Importantly, fingolimod (FTY720), a S1P analog recently approved for treatment of multiple sclerosis, also rapidly reduced P-glycoprotein activity; similar effects were found with the active, phosphorylated metabolite (FTY720P). We validated these findings in vivo using in situ brain perfusion in rats. Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, (3)H-verapamil (threefold increase), (3)H-loperamide (fivefold increase), and (3)H-paclitaxel (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain (14)C-sucrose accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

September 2012

Volume

109

Issue

39

Start / End Page

15930 / 15935

Related Subject Headings

  • Verapamil
  • Tumor Necrosis Factor-alpha
  • Tight Junctions
  • Sphingosine
  • Sphingolipids
  • Signal Transduction
  • Receptors, Lysosphingolipid
  • Rats, Sprague-Dawley
  • Rats
  • Propylene Glycols
 

Citation

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Chicago
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Cannon, R. E., Peart, J. C., Hawkins, B. T., Campos, C. R., & Miller, D. S. (2012). Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proceedings of the National Academy of Sciences of the United States of America, 109(39), 15930–15935. https://doi.org/10.1073/pnas.1203534109
Cannon, Ronald E., John C. Peart, Brian T. Hawkins, Christopher R. Campos, and David S. Miller. “Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain.Proceedings of the National Academy of Sciences of the United States of America 109, no. 39 (September 2012): 15930–35. https://doi.org/10.1073/pnas.1203534109.
Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proceedings of the National Academy of Sciences of the United States of America. 2012 Sep;109(39):15930–5.
Cannon, Ronald E., et al. “Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain.Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 39, Sept. 2012, pp. 15930–35. Epmc, doi:10.1073/pnas.1203534109.
Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proceedings of the National Academy of Sciences of the United States of America. 2012 Sep;109(39):15930–15935.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

September 2012

Volume

109

Issue

39

Start / End Page

15930 / 15935

Related Subject Headings

  • Verapamil
  • Tumor Necrosis Factor-alpha
  • Tight Junctions
  • Sphingosine
  • Sphingolipids
  • Signal Transduction
  • Receptors, Lysosphingolipid
  • Rats, Sprague-Dawley
  • Rats
  • Propylene Glycols