Cocaine potentiates cathepsin B secretion and neuronal apoptosis from HIV-infected macrophages.

TitleCocaine potentiates cathepsin B secretion and neuronal apoptosis from HIV-infected macrophages.
Publication TypeJournal Article
Year of Publication2014
AuthorsZenón, F, Segarra, AC, Gonzalez, M, Meléndez, LM
JournalJ Neuroimmune Pharmacol
Volume9
Issue5
Pagination703-15
Date Published2014 Dec
ISSN1557-1904
KeywordsAdult, Apoptosis, Biomarkers, Cathepsin B, Cells, Cultured, Cocaine-Related Disorders, Cohort Studies, Female, HIV Infections, HIV-1, Humans, Macrophages, Middle Aged, Neurons
Abstract

Substance abuse is a risk factor for HIV infection and progression to AIDS. Recent evidence establishes that cocaine use promotes brain perivascular macrophage infiltration and microglia activation. The lysosomal protease cathepsin B is increased in monocytes from patients with HIV dementia and its secretion induces 10-15% of neurotoxicity. Here we asked if cocaine potentiates cathepsin B secretion from HIV-infected monocyte-derived macrophages (MDM) and its effect in neuronal apoptosis. Samples of plasma, CSF, and post-mortem brain tissue from HIV positive patients that used cocaine were tested for cathepsin B and its inhibitors to determine the in vivo relevance of these findings. MDM were inoculated with HIV-1ADA, exposed to cocaine, and the levels of secreted and bioactive cathepsin B and its inhibitors were measured at different time-points. Cathepsin B expression (p < 0.001) and activity (p < 0.05) increased in supernatants from HIV-infected cocaine treated MDM compared with HIV-infected cocaine negative controls. Increased levels of cystatin B expression was also found in supernatants from HIV-cocaine treated MDM (p < 0.05). A significant increase in 30% of apoptotic neurons was obtained that decreased to 5% with the specific cathepsin B inhibitor (CA-074) or with cathepsin B antibody. Cathepsin B was significantly increased in the plasma and post-mortem brain tissue of HIV/cocaine users over non-drug users. Our results demonstrated that cocaine potentiates cathepsin B secretion in HIV-infected MDM and increase neuronal apoptosis. These findings provide new evidence that cocaine synergize with HIV-1 infection in increasing cathepsin B secretion and neurotoxicity.

DOI10.1007/s11481-014-9563-z
Alternate JournalJ Neuroimmune Pharmacol
PubMed ID25209871
PubMed Central IDPMC4209444
Grant List1-U54NS431 / NS / NINDS NIH HHS / United States
5U01MH083500 / MH / NIMH NIH HHS / United States
8G12-MD007600 / MD / NIMHD NIH HHS / United States
G12 MD007600 / MD / NIMHD NIH HHS / United States
G12 RR003051 / RR / NCRR NIH HHS / United States
N01MH32002 / MH / NIMH NIH HHS / United States
NS 38841 / NS / NINDS NIH HHS / United States
P20RR016470-12 / RR / NCRR NIH HHS / United States
R01 MH083516 / MH / NIMH NIH HHS / United States
R01MH083516 / MH / NIMH NIH HHS / United States
R24 NS45491 / NS / NINDS NIH HHS / United States
R24MH59724 / MH / NIMH NIH HHS / United States
R24MH59745 / MH / NIMH NIH HHS / United States
R25 GM061838 / GM / NIGMS NIH HHS / United States
R25GM061838 / GM / NIGMS NIH HHS / United States
U01 MH083500 / MH / NIMH NIH HHS / United States
U01 MH083501 / MH / NIMH NIH HHS / United States
U01 MH083506 / MH / NIMH NIH HHS / United States
U01 MH083507 / MH / NIMH NIH HHS / United States
U01 MH083545 / MH / NIMH NIH HHS / United States
U01MH083501 / MH / NIMH NIH HHS / United States
U01MH083506 / MH / NIMH NIH HHS / United States
U01MH083507 / MH / NIMH NIH HHS / United States
U01MH083545 / MH / NIMH NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States
U24 MH100929 / MH / NIMH NIH HHS / United States
U24 MH100931 / MH / NIMH NIH HHS / United States
U54 NS043011 / NS / NINDS NIH HHS / United States
U54NS043011 / NS / NINDS NIH HHS / United States