TY - JOUR
T1 - Sigma-1 Receptor Antagonist (BD1047) Decreases Cathepsin B Secretion in HIV-Infected Macrophages Exposed to Cocaine
AU - López, Omar Vélez
AU - Gorantla, Santhi
AU - Segarra, Annabell C.
AU - Andino Norat, María C.
AU - Álvarez, Manuel
AU - Skolasky, Richard L.
AU - Meléndez, Loyda M.
N1 - Funding Information:
Acknowledgements The authors would like to acknowledge the following funding sources: National Institutes of Health National Institute of General Medical Sciences (NIGMS) SC1GM113691, Translational Proteomics Center – National Institute of Mental Health (NIMH) G12-MD007600, MBRS-RISE Program-R25GM061838, University of Nebraska Medical Center Drug Abuse Center (Santhi Gorantla Ph.D.) National Institute of Drug Abuse (NIDA) 1R21DA041018-01, NSF PIRE OIRE #1545803, Annabell C Segarra), National Tissue Consortia including: Manhattan HIV Brain Bank: U01MH083501, R24MH59724, National Neurological AIDS Bank 5U01MH083500, NS 38841, California NeuroAIDS Tissue Network U01MH083506, R24MH597. We also thank the Comprehensive Cancer Center U54NS043011 for the state of the art research facilities and the PR Clinical and translational Research Consortium (PRCTRC) grant U54MD007587 from National Institute on Minority Health and Health Disparities (NIMHD) and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health for the clinical support in obtaining samples from HIV seronegative donors and for their partial support in obtaining the Nikon Eclipse E400, with a camera SPOT Insight QE and Fluorescence X-Cite Series 120 used in immunohistochemistry.
Funding Information:
The authors would like to acknowledge the following funding sources: National Institutes of Health National Institute of General Medical Sciences (NIGMS) SC1GM113691, Translational Proteomics Center – National Institute of Mental Health (NIMH) G12-MD007600, MBRS-RISE Program- R25GM061838, University of Nebraska Medical Center Drug Abuse Center (Santhi Gorantla Ph.D.) National Institute of Drug Abuse (NIDA) 1R21DA041018-01, NSF PIRE OIRE #1545803, Annabell C Segarra), National Tissue Consortia including: Manhattan HIV Brain Bank: U01MH083501, R24MH59724, National Neurological AIDS Bank 5U01MH083500, NS 38841, California NeuroAIDS Tissue Network U01MH083506, R24MH597. We also thank the Comprehensive Cancer Center U54NS043011 for the state of the art research facilities and the PR Clinical and translational Research Consortium (PRCTRC) grant U54MD007587 from National Institute on Minority Health and Health Disparities (NIMHD) and the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health for the clinical support in obtaining samples from HIV seronegative donors and for their partial support in obtaining the Nikon Eclipse E400, with a camera SPOT Insight QE and Fluorescence X-Cite Series 120 used in immunohistochemistry.
Publisher Copyright:
© 2018, The Author(s).
PY - 2019/6/15
Y1 - 2019/6/15
N2 - 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. [Figure not available: see fulltext.].
AB - 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. [Figure not available: see fulltext.].
KW - Cathepsin B
KW - Cocaine
KW - HAND
KW - HIV-1
KW - Sigma-1 receptor
UR - http://www.scopus.com/inward/record.url?scp=85055107200&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055107200&partnerID=8YFLogxK
U2 - 10.1007/s11481-018-9807-4
DO - 10.1007/s11481-018-9807-4
M3 - Article
C2 - 30306495
AN - SCOPUS:85055107200
VL - 14
SP - 226
EP - 240
JO - Journal of NeuroImmune Pharmacology
JF - Journal of NeuroImmune Pharmacology
SN - 1557-1890
IS - 2
ER -