Rapid and reversible enhancement of blood-brain barrier permeability using lysophosphatidic acid

Ngoc H. On, Sanjot Savant, Myron Toews, Donald W. Miller

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

The present study characterizes the effects of lysophosphatidic acid (LPA) on blood-brain barrier (BBB) permeability focusing specifically on the time of onset, duration, and magnitude of LPA-induced changes in cerebrovascular permeability in the mouse using both magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIFR). Furthermore, potential application of LPA for enhanced drug delivery to the brain was also examined by measuring the brain accumulation of radiolabeled methotrexate. Exposure of primary cultured brain microvessel endothelial cells (BMECs) to LPA produced concentration-dependent increases in permeability that were completely abolished by clostridium toxin B. Administration of LPA disrupted BBB integrity and enhanced the permeability of small molecular weight marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRdye800cwPEG, and the P-glycoprotein efflux transporter probe, Rhodamine 800 (R800). The increase in BBB permeability occurred within 3 minutes after LPA injection and barrier integrity was restored within 20 minutes. A decreased response to LPA on large macromolecule BBB permeability was observed after repeated administration. The administration of LPA also resulted in 20-fold enhancement of radiolabeled methotrexate in the brain. These studies indicate that administration of LPA in combination with therapeutic agents may increase drug delivery to the brain.

Original languageEnglish (US)
Pages (from-to)1944-1954
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number12
DOIs
StatePublished - Dec 2013

Keywords

  • Blood-brain barrier
  • Lysophosphatidic acid
  • Magnetic resonance imaging
  • Near infrared fluorescence imaging
  • Permeability

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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