title: Methamphetamine-induced nitric oxide promotes vesicular transport in blood-brain barrier endothelial cells.
abstract: Methamphetamine's (METH) neurotoxicity is thought to be in part due to its ability to induce blood-brain barrier (BBB) dysfunction. Here, we investigated the effect of METH on barrier properties of cultured rat primary brain microvascular endothelial cells (BMVECs). Transendothelial flux doubled in response to METH, irrespective of the size of tracer used. At the same time, transendothelial electrical resistance was unchanged as was the ultrastructural appearance of inter-endothelial junctions and the distribution of key junction proteins, suggesting that METH promoted vesicular but not junctional transport. Indeed, METH significantly increased uptake of horseradish peroxidase into vesicular structures. METH also enhanced transendothelial migration of lymphocytes indicating that the endothelial barrier against both molecules and cells was compromised. Barrier breakdown was only observed in response to METH at low micromolar concentrations, with enhanced vesicular uptake peaking at 1 μM METH. The BMVEC response to METH also involved rapid activation of endothelial nitric oxide synthase and its inhibition abrogated METH-induced permeability and lymphocyte migration, indicating that nitric oxide was a key mediator of BBB disruption in response to METH. This study underlines the key role of nitric oxide in BBB function and describes a novel mechanism of drug-induced fluid-phase transcytosis at the BBB.
authors.affiliation: Cell Biology, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Tânia
authors.initials: T
authors.lastname: Martins
authors.forename: Thomas
authors.initials: T
authors.lastname: Burgoyne
authors.forename: Bridget-Ann
authors.initials: BA
authors.lastname: Kenny
authors.forename: Natalie
authors.initials: N
authors.lastname: Hudson
authors.forename: Clare E
authors.initials: CE
authors.lastname: Futter
authors.forename: António F
authors.initials: AF
authors.lastname: Ambrósio
authors.forename: Ana P
authors.initials: AP
authors.lastname: Silva
authors.forename: John
authors.initials: J
authors.lastname: Greenwood
authors.forename: Patric
authors.initials: P
authors.lastname: Turowski
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D008694:Methamphetamine / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D011917:Rats, Inbred Lew; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism*
chemical_list: D009569:Nitric Oxide; D008694:Methamphetamine; D019331:NG-Nitroarginine Methyl Ester