Methamphetamine Disrupts Blood–Brain Barrier Function by Induction of Oxidative Stress in Brain Endothelial Cells

Abstract

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. Here we provide evidence that METH alters BBB function via 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 microvascular endothelial cells (BMVEC) to METH diminishes tightness of BMVEC monolayers in a dose- and time-dependent manner by decreasing expression of cell membrane associated tight junction (TJ) proteins. These changes were accompanied by enhanced production of reactive oxygen species, increased monocyte migration across METH-treated endothelial monolayers, and activation of myosin light chain kinase (MLCK) in BMVEC. Anti-oxidant 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.

Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

“…In endothelial cells, these events may lead to loss of adhesion and/or relevant restructuration of the endothelium, thus contributing to increase METH neurotoxicity. Interestingly, although METH-induced internalization of both claudin and occludin through endocytosis was previously seen to be concomitant with TJ fragmentation and gap formation [3,13,14], the functional significance of such translocation remains unclear, since it can occur also in the absence of BBB structural changes [15]. As the anchoring protein ZO-1 and the transmembrane protein occludin are physically linked to the actin filaments, some authors have hypothesized that actin depolymerization could be secondary to the loss of these binding interactions.…”

“…ALC Prevented the METH-Induced Loss and Redistribution of Claudin-5 METH-induced changes in claudin-5 were previously reported [3,9,10]. Here, we aimed to assess the effect of ALC 1 mM in preventing these changes.…”

“…Both short-and long-term METH uses lead to long-lasting deleterious effects [1,2]. METH toxicity is typically characterized by disruption of synaptic integrity and decreased monoamine production [3][4][5], concomitant with terminal degeneration and neuronal death [2, Electronic supplementary material The online version of this article (doi:10.1007/s12035-014-8973-5) contains supplementary material, which is available to authorized users. 6].…”

“…6]. METH is increasingly recognized to impact also nonneuronal cells, such as microglia, and astrocytes and the blood-brain-barrier (BBB), causing the release of inflammatory mediators and astrogliosis [1,3,7,8]. The concept of METH-induced damage at the level of the BBB has gained relevance over the last few years, justifying the interest in understanding its consequences at the endothelium [4,9,10].…”

Methamphetamine promotes α-tubulin deacetylation in endothelial cells: The protective role of acetyl-l-carnitine

“…METH toxicity is characterized by the disruption of the dopaminergic system, concomitant with terminal degeneration and eventual neuronal death (Conant et al, 2011;Krasnova and Cadet, 2009). However, METH has been increasingly recognized to impact also the blood-brain-barrier (BBB), causing the release of inflammatory mediators and astrogliosis (Gold et al, 2009;Goncalves et al, 2010;Northrop and Yamamoto, 2012;Ramirez et al, 2009). METH-induced permeability at the BBB level has been consistently reported both in vivo and in vitro (Conant et al, 2011;Martins et al, 2011;Urrutia et al, 2013), as a result of tight junction and cytoskeleton disarrangement (Dietrich, 2009;Kousik et al, 2012;Park et al, 2013).…”