title: Cocaine potentiates cathepsin B secretion and neuronal apoptosis from HIV-infected macrophages.
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.
authors.affiliation: Department of Microbiology and Medical Zoology, School of Medicine, University of Puerto Rico Medical Sciences Campus, PO Box 365067, San Juan, Puerto Rico.
authors.forename: Frances
authors.initials: F
authors.lastname: Zenón
authors.forename: Annabell C
authors.initials: AC
authors.lastname: Segarra
authors.forename: Mariangeline
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Loyda M
authors.initials: LM
authors.lastname: Meléndez
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000502:physiology; D015415:Biomarkers / Q000097:blood; D002401:Cathepsin B / Q000097:blood*; D002478:Cells, Cultured; D019970:Cocaine-Related Disorders / Q000097:blood* / Q000175:diagnosis; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000175:diagnosis; D015497:HIV-1; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000821:virology
chemical_list: D015415:Biomarkers; C533912:CTSB protein, human; D002401:Cathepsin B