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Our laboratory has demonstrated increased expression of cathepsin B (CATB) in postmortem brain tissue with HAND. Increased secretion of CATB from in vitro HIV-infected monocyte-derived macrophages (MDM) induces neurotoxicity. Activation of cannabinoid receptor type 2 (CB2R) inhibits HIV-1 replication in macrophages and the neurotoxicity induced by viral proteins. However, it is unknown if CB2R agonists affect CATB secretion and neurotoxicity in HIV-infected MDM. <jats:italic>We hypothesized that HIV-infected MDM exposed to CB2R agonists decrease CATB secretion and neurotoxicity.<\/jats:italic> Primary MDM were inoculated with HIV-1<jats:sub>ADA<\/jats:sub> and treated with selective CB2R agonists JWH-133 and HU-308. HIV-1 p24 and CATB levels were determined from supernatants using ELISA. MDM were pre-treated with a selective CB2R antagonist SR144528 before JWH-133 treatment to determine if CB2R activation is responsible for the effects. Neuronal apoptosis was assessed using a TUNEL assay. Results show that both agonists reduce HIV-1 replication and CATB secretion from MDM in a time and dose-dependent manner and that CB2R activation is responsible for these effects. Finally, JWH-133 decreased HIV\/MDM-CATB induced neuronal apoptosis. Our results suggest that agonists of CB2R represent a potential therapeutic strategy against HIV\/MDM-induced neurotoxicity.<\/jats:p>","DOI":"10.1038\/s41598-021-03896-3","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T11:03:21Z","timestamp":1641553401000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cannabinoid receptor type 2 agonist JWH-133 decreases cathepsin B secretion and neurotoxicity from HIV-infected macrophages"],"prefix":"10.1038","volume":"12","author":[{"given":"Lester J.","family":"Rosario-Rodr\u00edguez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yamil","family":"Gerena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis A.","family":"Garc\u00eda-Requena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luz J.","family":"Cartagena-Isern","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan C.","family":"Cuadrado-Ruiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Borges-V\u00e9lez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loyda M.","family":"Mel\u00e9ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,1,7]]},"reference":[{"key":"3896_CR1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318200d727","author":"RK Heaton","year":"2010","unstructured":"Heaton, R. 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