Sigma-1 Receptor Antagonist (BD1047) Decreases Cathepsin B Secretion in HIV-Infected Macrophages Exposed to Cocaine
Year: 2018
Type: article
Abstract: Pathogenesis of HIV-associated neurocognitive disorders (HAND) is mediated through the infiltration of perivascular macrophages into the brain with the secretion of viral, neurotoxic and inflammatory proteins. One of these proteins is cathepsin B (CATB), a lysosomal cysteine protease that induces neuronal apoptosis, and increases in plasma and cerebrospinal fluid from HIV-1 infected patients (Cantres-Rosario et al. AIDS 27(3):347–356, 2013). Cocaine further potentiates CATB neurotoxicity in vitro and in vivo (Zenón et al. J NeuroImmune Pharmacol 9(5):703–715, 2014). Modulation of sigma-1 (Sig1R) by cocaine increases oxidative species, cytokines and other factors that promote lysosomal disruption. However, the role of Sig1R in CATB secretion and HIV-1 replication in macrophages exposed to cocaine is unknown. We hypothesized that pharmacological modulation of Sig1R would alter CATB secretion from HIV-1 infected macrophages in vitro and in vivo. To test our hypothesis, monocyte derived-macrophages (MDM) from HIV-1 seronegative donors were isolated, infected with HIV-1ADA, and pretreated with Sig1R antagonist (BD1047) or Sig1R agonist (PRE-084) prior to cocaine exposure and followed for 3,6,9 and 11 days post-infection (dpi). Experiments in vivo were conducted using the HIV encephalitis mouse model (HIVE) with BD1047 treatments prior to cocaine for 14 days. Results demonstrate that in presence of cocaine, BD1047 decreases CATB secretion at 11 dpi, while PRE-084 did not have an effect. In the mouse model, BD1047 treatment prior to cocaine decreased CATB expression, cleaved caspase-3 an p24 antigen levels, reduced astrocytosis, but did not increase MAP-2 or synaptophysin. Results demonstrate that Sig1R plays a role in the modulation of CATB levels in HIV-1 infected MDM exposed to cocaine in vitro and in vivo.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
Funders: National Science Foundation, University of Nebraska Medical Center, National Institutes of Health, National Institute on Aging, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute on Minority Health and Health Disparities
Awards: California NeuroAIDS Tissue Network (CNTN), G1684841429, G1877118742, G2041095871, Center for Humanized Mice, G2172600091, PIRE: Neural Mechanisms of Reward and Decision, G296576338, California NeuroAIDS Tissue Network, G3471390838, National Neurological AIDS Bank, G4140207963, The Manahattan HIV Brain Bank, G4379057272, The Manhattan HIV Brain Bank, G4626340976, G4986506763, G4989853375, 18th-22nd Conferences: Drug Abuse, Immune Modulation and AIDS, G5954914948, A Caribbean Project for Clinical and Basic Neuroscience Research, SMART HAND, G7161053304, G8162860740, G880511130, G886786700, G9000043731, G9000053804, G9000132119, G9000151750, G9000156444, Center for Collaborative Research in Health Disparities
OpenAlex ID: W2897347356