Date Published:
2014 Dec

Publication Type:
Journal Article

Authors:

F. Zenón
A.C. Segarra
M. Gonzalez
L.M. Meléndez

Secondary:
J Neuroimmune Pharmacol

Volume:
9

Pagination:
703-15

Issue:
5

PMID:
25209871

URL:
https://pubmed.ncbi.nlm.nih.gov/25209871

DOI:
10.1007/s11481-014-9563-z

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:
<p>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.</p>