Methamphetamine disrupts blood-brain barrier function by induction of oxidative stress in brain endothelial cells.
Methamphetamine (METH), a potent stimulant with strong euphoric properties, has a high abuse liability and long-lasting neurotoxic effects. Recent studies in animal models have indicated that METH can induce impairment of the blood-brain barrier (BBB), thus suggesting that some of the neurotoxic effects resulting from METH abuse could be the outcome of barrier disruption. In this study, we provide evidence that METH alters BBB function through direct effects on endothelial cells and explore possible underlying mechanisms leading to endothelial injury. We report that METH increases BBB permeability in vivo, and exposure of primary human brain microvascular endothelial cells (BMVEC) to METH diminishes the tightness of BMVEC monolayers in a dose- and time-dependent manner by decreasing the expression of cell membrane-associated tight junction (TJ) proteins. These changes were accompanied by the enhanced production of reactive oxygen species, increased monocyte migration across METH-treated endothelial monolayers, and activation of myosin light chain kinase (MLCK) in BMVEC. Antioxidant treatment attenuated or completely reversed all tested aspects of METH-induced BBB dysfunction. Our data suggest that BBB injury is caused by METH-mediated oxidative stress, which activates MLCK and negatively affects the TJ complex. These observations provide a basis for antioxidant protection against brain endothelial injury caused by METH exposure.
Ramirez
Servio H
SH
Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Potula
Raghava
R
Fan
Shongshan
S
Eidem
Tess
T
Papugani
Anil
A
Reichenbach
Nancy
N
Dykstra
Holly
H
Weksler
Babette B
BB
Romero
Ignacio A
IA
Couraud
Pierre O
PO
Persidsky
Yuri
Y
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000378:metabolism; D002839:Chromans / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008694:Methamphetamine / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000975:Antioxidants; D000697:Central Nervous System Stimulants; D002839:Chromans; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D008694:Methamphetamine; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid