Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

P M Abdul Muneer,Saleena Alikunju,James Haorah,Adam M Szlachetka,L Charles Murrin

doi:10.1186/1750-1326-6-23

P M Abdul Muneer, Saleena Alikunju + Show 3 more

Open Access

https://doi.org/10.1186/1750-1326-6-23

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Abstract

BackgroundMethamphetamine (METH), an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB) function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB) to date.ResultsIn this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM) increased the expression of glucose transporter protein-1 (GLUT1) in primary human brain endothelial cell (hBEC, main component of BBB) without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB) aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function.ConclusionOur findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

Highlights

Methamphetamine (METH), an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation
Effects of METH on glucose uptake and glucose transporter protein-1 (GLUT1) expression We first examined the dose-dependent effect of METH (5 - 500 μM) exposure for 24 hr on glucose uptake by primary human brain endothelial cell culture
We examined the effects of these two METH concentrations on glucose uptake by human brain endothelial cell (hBEC) with/ without cytochalasin B (CB, glucose transporter protein (GLUT) inhibitor) and acetylL-carnitine (ALC, neuroprotective agent)

Summary

Introduction

Methamphetamine (METH), an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Methamphetamine (METH), a highly addictive drug is a potent CNS stimulant that produces euphoric effects by promoting the release of dopamine, serotonin and norepinephrine [1]. The ability of METH to stimulate the release of dopamine rapidly from dopaminergic neurons in the reward regions of the brain produces intense euphoric effects [3]. Acute bingeing and chronic self-administration paradigms of METH abuse cause severe neurotoxicity, monoamine deficits, hyperthermia, cardiac arrhythmia, depression, addiction, and psychiatric problems due to neuronal damage [4]. Multiple mechanisms of METH-induced neurotoxicity have been reported including hyperthermia, dopamine depletion, microglial activation, free radical formation, intrinsic cell apoptosis, and cytokine production [5,6]. METH abuse is shown to exert neurotoxic effects by increasing the secretion of pro-inflammatory cytokines IL-6 and TNF-alpha in the brain [15,16]

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