The TNF-α/Nf-κB Signaling Pathway has a Key Role in Methamphetamine–Induced Blood–Brain Barrier Dysfunction

Abstract

Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood-brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction.

Melatonin promotes blood-brain barrier integrity in methamphetamine-induced inflammation in primary rat brain microvascular endothelial cells

“…The nuclear factor-ĸB (NF-κB) signaling is the major pathway that regulates the inflammatory cytokine expression and has been widely studied in inflammatory responses (Kawai and Akira, 2007). Previous studies have reported several stimuli such as lipopolysaccharide (LPS) and METH-induced inflammation in both neuronal cells and glial cells by the overactivation of NF-κB signaling (Flora et al, 2003;Shah et al, 2012;Wires et al, 2012;Perpoonpattana et al, 2013;Coelho-Santos et al, 2015;Jumnongprakhon et al, 2015). Therefore, the inhibition of these negative effects may be beneficial in protecting BBB impairment.…”

WITHDRAWN: Melatonin improves methamphetamine-induced blood brain barrier impairment through NADPH oxidase-2 in primary rat brain microvascular endothelium cells

“…BBB impairment by METH has been reviewed in several mechanisms, including the hyperactivity of NADPH oxidase (NOX)-2 which generates excessive amounts of free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Ramirez et al, 2009;Park et al, 2012); the dysfunction of cytoskeleton and the transmembrane protein of tight junction, which is the controlling of paracellular permeability (Park et al, 2013;Fernandes et al, 2015); the dysfunction of the uptake and the efflux activities (Elali et al, 2012); and the activation of caspase cascade in cell death response or apoptosis (Abdul et al, 2011;Ma et al, 2014;Fisher et al, 2015). Moreover, overexpression of inflammatory mediators such as inducible nitric oxide synthase (iNOS), nitric oxide (NO), interleukin (IL)-1, and tumor necrosis factor (TNF) α, which is an important factor in inflammatory response, has also been reported (Fernandes et al, 2014;Coelho-Santos et al, 2015;Parikh et al, 2015;Zhang et al, 2015;Skaper et al, 2014;Hussain et al, 2015;Kothur et al, 2015).…”

“…Previous studies have reported several stimuli such as lipopolysaccharide (LPS) and METHinduced inflammation in both neuronal cells and glial cells by the overactivation of NF-κB signaling (Flora et al, 2003;Shah et al, 2012;Wires et al, 2012;Permpoonpattana et al, 2013;Coelho-Santos et al, 2015;Jumnongprakhon et al, 2015). Therefore, the inhibition of these negative effects may be beneficial in protecting BBB impairment.…”

Drugs of abuse and blood-brain barrier endothelial dysfunction: A focus on the role of oxidative stress

“…with 2-h interval on a single day) resulted in altered and weakened structure of brain microvessels with increased permeability to plasma proteins. 68 In addition, acute (10 mg/kg, i.p.) or chronic METH exposure (15 mg/kg, i.p.)…”

“…An important downstream effect of METH-induced NF-kB activity is a rapid and pronounced inflammatory response through secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFa) in BBB endothelial cells, 68,76 which critically downregulate TJ proteins and compromise the BBB integrity. 77,78 In this inflammatory landscape where cytokines activate NADPH oxidase-dependent oxidative stress, 79 TNFa release mediates both paracellular and transcellular (vesicular) permeability of BBB following acute METH exposure at relatively low doses (1 mM), which was blocked by NF-kB inhibitor.…”