Methamphetamine alters blood brain barrier permeability via the modulation of tight junction expression: Implication for HIV-1 neuropathogenesis in the context of drug abuse

Abstract

The pathogenesis of human immunodeficiency virus (HIV) associated encephalopathy is attributed to infiltration of the central nervous system (CNS) by HIV-1 infected mononuclear cells that transmigrate across the blood brain barrier (BBB). The endothelial tight junctions (TJ) of the blood brain barrier (BBB) play a critical role in controlling cellular traffic into the CNS. Neuropathogenesis of HIV-1 is exacerbated by drugs of abuse such as methamphetamine (Meth) which are capable of dysregulating BBB function. HIV-1 viral proteins like gp120 are both neurotoxic and cytotoxic and have been implicated in the development of HIV-1 dementia (HAD). We hypothesize that gp120 in synergy with Meth can alter BBB permeability via the modulation of tight junction expression. We investigated the effect of Meth and/or gp120 on the basal expression of TJ proteins ZO-1, JAM-2, Occludin, Claudin-3 and Claudin-5, using in vitro cultures of the primary brain microvascular endothelial cells (BMVEC). Further, the functional effects of TJ modulation were assessed using an in vitro BBB model, that allowed measurement of BBB permeability using TEER measurements and transendothelial migration of immunocompetent cells. Our results show that both Meth and gp120 individually and in combination, modulated TJ expression, and these effects involved Rho-A activation. Further, both Meth and gp120 alone and in combination significantly decreased transendothelial resistance across the in vitro BBB and the enhanced transendothelial migration of immunocompetent cells across the BBB. An understanding of the mechanisms of BBB breakdown that lead to neurotoxicity is crucial to the development of therapeutic modalities for Meth abusing HAD patients.

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

“…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.…”

“…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].…”

“…The endothelial paracellular permeability occurs due to the equilibrium between cytoskeleton contractile forces and adhesive forces produced at the endothelial cellcell junctions and cell-matrix contacts [14], where actin filaments play an essential role. Functioning as a cross-linker between occludin and the actin cytoskeleton, the protein ZO-1 is also central to the TJ structure [10,13,18,23].…”

“…Importantly, METH-induced BBB increased permeability was associated with reduction and/or redistribution of TJ proteins [10,13]. There is also evidence that it can interfere with actin structure and arrangement, which also may lead to compromised TJ function [14,26].…”

Formative Assessment of ARM-U: A Modular Intervention for Decreasing Risk Behaviors Among HIV-Positive and HIV-Negative Methamphetamine- Using MSM

“…Methamphetamine use has been associated with both transmission and acquisition of HIV among MSM [2,3,9,10]. Recent studies have also shown methamphetamine use to increase the rate of progression of HIV disease [11][12][13][14]. Reports of four major U.S. cities found 9.5% of MSM reported methamphatimine use within the past 6 months [15].…”