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.
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Acknowledgments
Sponsored by grants from the National Institutes of Health R01MH083516 (L.M.M.), U54NS043011, RISE Program R25GM061838 (FZ.), SNRP-NINDS-1-U54NS431, INBRE P20RR016470-12, NIMHHD 8G12-MD007600 Translational Proteomics Center, and grants ISI0 RR-13705-01 and DBI-0923132 to establish and upgrade the Confocal Microscopy Facility at the University of Puerto Rico (CIF-UPR). UPR Vice President (M.P.), UPR Medical Sciences Campus Chancellor, and the Associate Deanship of Biomedical Sciences provided additional funding to complete this study. We thank the PI of the Hispanic Women cohort, Dr. Valerie Wojna for following the study patients. This publication was made possible from NIH funding through the NIMH and NINDS Institutes by the following grants:
Manhattan HIV Brain Bank: U01MH083501, R24MH59724
Texas NeuroAIDS Research Center U01MH083507, R24 NS45491
National Neurological AIDS Bank 5U01MH083500, NS 38841
California NeuroAIDS Tissue Network U01MH083506, R24MH59745
Statistics and Data Coordinating Center U01MH083545, N01MH32002
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Zenón, F., Segarra, A.C., Gonzalez, M. et al. Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages. J Neuroimmune Pharmacol 9, 703–715 (2014). https://doi.org/10.1007/s11481-014-9563-z
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DOI: https://doi.org/10.1007/s11481-014-9563-z