ArticleProceedings of the National Academy of Sciences of the United States of America2012
Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
78 citing papers in PubMed, 1 synthesis or guideline pooled it, 141 citations in OpenAlex.
- The efficacy and safety of fingolimod plus standardized treatment versus standardized treatment alone for acute ischemic stroke: A systematic review and meta-analysis.Pharmacology research & perspectives · 2022Pooled it
- Combination of the Immune Modulator Fingolimod With Alteplase in Acute Ischemic Stroke: A Pilot Trial.Circulation · 2015Trial
- Neisseria meningitidis regulates P-glycoprotein transporter activity in brain endothelial cells via sphingosine 1-phosphate receptor 1.Fluids and barriers of the CNS · 2025Article
- Innate immune sensors and regulators at the blood brain barrier: focus on toll-like receptors and inflammasomes as mediators of neuro-immune crosstalk and inflammation.Journal of neuroinflammation · 2025Review
- The sphingosine-1-phosphate signaling pathway (sphingosine-1-phosphate and its receptor, sphingosine kinase) and epilepsy.Epilepsia open · 2025Review
- Pharmacokinetic Study of Fingolimod Nasal Films Administered via Nose-to-Brain Route in C57BL/6 J Mice as Potential Treatment for Multiple Sclerosis.Pharmaceutical research · 2024Article
- Coupling the role of lipids to the conformational dynamics of the ABC transporter P-glycoprotein.Biophysical journal · 2024Article
- Nongenomic ERα-AMPK Signaling Regulates Sex-Dependent Bcrp Transport Activity at the Blood-Brain Barrier.Endocrinology · 2024Article
- Phospholipidomics in Clinical Trials for Brain Disorders: Advancing our Understanding and Therapeutic Potentials.Molecular neurobiology · 2024Review
- Article
- ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier: Potential New Targets to Improve Brain Drug Delivery.Pharmacological reviews · 2023Review
- Immune System and Brain/Intestinal Barrier Functions in Psychiatric Diseases: Is Sphingosine-1-Phosphate at the Helm?International journal of molecular sciences · 2023Review
- Central Versus Peripheral Drug Exposure Ratio, a Key Differentiator for Siponimod Over Fingolimod?Neurology and therapy · 2023Article
- Measurement and Modeling of Transport Across the Blood-Brain Barrier.Journal of biomechanical engineering · 2023Review
- Experimental Models of In Vitro Blood-Brain Barrier for CNS Drug Delivery: An Evolutionary Perspective.International journal of molecular sciences · 2023Review
- Advances in Antibody-Based Therapeutics for Cerebral Ischemia.Pharmaceutics · 2022Review
- Regulation of P-Glycoprotein in the Brain.International journal of molecular sciences · 2022Review
- Expression and functions of adenylyl cyclases in the CNS.Fluids and barriers of the CNS · 2022Review
- Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2021Review
- Development of Novel Therapeutics Targeting the Blood-Brain Barrier: From Barrier to Carrier.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2021Review
18 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
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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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.