{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:28:30Z","timestamp":1790951310164,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T00:00:00Z","timestamp":1699833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004576","name":"Ministry of Agriculture and Rural Development (Israel)","doi-asserted-by":"publisher","award":["16-18-0001"],"award-info":[{"award-number":["16-18-0001"]}],"id":[{"id":"10.13039\/501100004576","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cannabidiol (CBD), the major non-psychoactive phytocannabinoid found in cannabis, has anti-neuroinflammatory properties. Despite the increasing use of CBD, little is known about its effect in combination with other substances. Combination therapy has been gaining attention recently, aiming to produce more efficient effects. Angiotensin II activates the angiotensin 1 receptor and regulates neuroinflammation and cognition. Angiotensin receptor 1 blockers (ARBs) were shown to be neuroprotective and prevent cognitive decline. The present study aimed to elucidate the combined role of CBD and ARBs in the modulation of lipopolysaccharide (LPS)-induced glial inflammation. While LPS significantly enhanced nitric oxide synthesis vs. the control, telmisartan and CBD, when administered alone, attenuated this effect by 60% and 36%, respectively. Exposure of LPS-stimulated cells to both compounds resulted in the 95% inhibition of glial nitric oxide release (additive effect). A synergistic inhibitory effect on nitric oxide release was observed when cells were co-treated with losartan (5 \u03bcM) and CBD (5 \u03bcM) (by 80%) compared to exposure to each compound alone (by 22% and 26%, respectively). Telmisartan and CBD given alone increased TNF\u03b1 levels by 60% and 40%, respectively. CBD and telmisartan, when given together, attenuated the LPS-induced increase in TNF\u03b1 levels without statistical significance. LPS-induced IL-17 release was attenuated by CBD with or without telmisartan (by 75%) or telmisartan alone (by 60%). LPS-induced Interferon-\u03b3 release was attenuated by 80% when telmisartan was administered in the absence or presence of CBD. Anti-inflammatory effects were recorded when CBD was combined with the known anti-inflammatory agent dimethyl fumarate (DMF)\/monomethyl fumarate (MMF). A synergistic inhibitory effect of CBD and MMF on glial release of nitric oxide (by 77%) was observed compared to cells exposed to MMF (by 35%) or CBD (by 12%) alone. Overall, this study highlights the potential of new combinations of CBD (5 \u03bcM) with losartan (5 \u03bcM) or MMF (1 \u03bcM) to synergistically attenuate glial NO synthesis. Additive effects on NO production were observed when telmisartan (5 \u03bcM) and CBD (5 \u03bcM) were administered together to glial cells.<\/jats:p>","DOI":"10.3390\/ijms242216254","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T08:35:52Z","timestamp":1699864552000},"page":"16254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["An Emerging Strategy for Neuroinflammation Treatment: Combined Cannabidiol and Angiotensin Receptor Blockers Treatments Effectively Inhibit Glial Nitric Oxide Release"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0797-8816","authenticated-orcid":false,"given":"Sigal","family":"Fleisher-Berkovich","sequence":"first","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Battaglia","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Torino, 10124 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5483-8501","authenticated-orcid":false,"given":"Francesca","family":"Baratta","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Torino, 10124 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6266-4492","authenticated-orcid":false,"given":"Paola","family":"Brusa","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Torino, 10124 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne","family":"Ventura","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitzan","family":"Sharon","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-3514","authenticated-orcid":false,"given":"Arik","family":"Dahan","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8782-3496","authenticated-orcid":false,"given":"Massimo","family":"Collino","sequence":"additional","affiliation":[{"name":"Department of Neuroscience \u201cRita Levi Montalcini\u201d, University of Torino, 10124 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7551-5488","authenticated-orcid":false,"given":"Shimon","family":"Ben-Shabat","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.biocel.2004.07.009","article-title":"The role of inflammation in Alzheimer\u2019s disease","volume":"37","author":"Tuppo","year":"2005","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"470S","DOI":"10.1093\/ajcn\/83.2.470S","article-title":"Inflammation and neurodegenerative diseases","volume":"83","author":"Griffin","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41582-020-00435-y","article-title":"Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here?","volume":"17","author":"Leng","year":"2021","journal-title":"Nat. Rev. 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