title: 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.
authors.affiliation: Department of Medicine, Division of Allergy, Immunology, and Rheumatology, 301 Multi Research Building, Buffalo General Hospital, 100 High Street, Buffalo, NY 14203, USA. smahajan@buffalo.edu
authors.forename: Supriya D
authors.initials: SD
authors.lastname: Mahajan
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Aalinkeel
authors.forename: Donald E
authors.initials: DE
authors.lastname: Sykes
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Reynolds
authors.forename: B
authors.initials: B
authors.lastname: Bindukumar
authors.forename: Adaffaras
authors.initials: A
authors.lastname: Adal
authors.forename: Mingshen
authors.initials: M
authors.lastname: Qi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Toh
authors.forename: Gaixia
authors.initials: G
authors.lastname: Xu
authors.forename: Paras N
authors.initials: PN
authors.lastname: Prasad
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Schwartz
mesh_terms: D000704:Analysis of Variance; D001812:Blood-Brain Barrier / Q000166:cytology* / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008694:Methamphetamine / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D015699:HIV Envelope Protein gp120; D008565:Membrane Proteins; D008694:Methamphetamine