Cocaine potentiates cathepsin B secretion and neuronal apoptosis from HIV-infected macrophages.
Title | Cocaine potentiates cathepsin B secretion and neuronal apoptosis from HIV-infected macrophages. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Zenón, F, Segarra, AC, Gonzalez, M, Meléndez, LM |
Journal | J Neuroimmune Pharmacol |
Volume | 9 |
Issue | 5 |
Pagination | 703-15 |
Date Published | 2014 Dec |
ISSN | 1557-1904 |
Keywords | Adult, Apoptosis, Biomarkers, Cathepsin B, Cells, Cultured, Cocaine-Related Disorders, Cohort Studies, External, 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. |
DOI | 10.1007/s11481-014-9563-z |
Alternate Journal | J Neuroimmune Pharmacol |
PubMed ID | 25209871 |
PubMed Central ID | PMC4209444 |
Grant List | U24 MH100929 / MH / NIMH NIH HHS / United States U01 MH083507 / MH / NIMH NIH HHS / United States U01 MH083500 / MH / NIMH NIH HHS / United States U24 MH100931 / MH / NIMH NIH HHS / United States R01MH083516 / MH / NIMH NIH HHS / United States R25 GM061838 / GM / NIGMS NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States 5U01MH083500 / MH / NIMH NIH HHS / United States R24MH59724 / MH / NIMH NIH HHS / United States R24MH59745 / MH / NIMH NIH HHS / United States U54 NS043011 / NS / NINDS NIH HHS / United States U54NS043011 / NS / NINDS NIH HHS / United States 1-U54NS431 / NS / NINDS NIH HHS / United States P20RR016470-12 / RR / NCRR NIH HHS / United States R24 NS45491 / NS / NINDS NIH HHS / United States NS 38841 / NS / NINDS NIH HHS / United States R25GM061838 / GM / NIGMS NIH HHS / United States G12 RR003051 / RR / NCRR NIH HHS / United States U01MH083501 / MH / NIMH NIH HHS / United States U01 MH083501 / MH / NIMH NIH HHS / United States U01MH083506 / MH / NIMH NIH HHS / United States U01 MH083545 / MH / NIMH NIH HHS / United States U01 MH083506 / MH / NIMH NIH HHS / United States R01 MH083516 / MH / NIMH NIH HHS / United States U01MH083507 / MH / NIMH NIH HHS / United States G12 MD007600 / MD / NIMHD NIH HHS / United States U01MH083545 / MH / NIMH NIH HHS / United States 8G12-MD007600 / MD / NIMHD NIH HHS / United States |