title: HU-446 and HU-465, Derivatives of the Non-psychoactive Cannabinoid Cannabidiol, Decrease the Activation of Encephalitogenic T Cells.
abstract: Cannabidiol (CBD), the non-psychoactive cannabinoid, has been previously shown by us to decrease peripheral inflammation and neuroinflammation in mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Here we have studied the anti-inflammatory effects of newly synthesized derivatives of natural (-)-CBD ((-)-8,9-dihydro-7-hydroxy-CBD; HU-446) and of synthetic (+)-CBD ((+)-8,9-dihydro-7-hydroxy-CBD; HU-465) on activated myelin oligodendrocyte glycoprotein (MOG)35-55-specific mouse encephalitogenic T cells (T(MOG) ) driving EAE/MS-like pathologies. Binding assays followed by molecular modeling revealed that HU-446 has negligible affinity toward the cannabinoid CB1 and CB2 receptors while HU-465 binds to both CB1 and CB2 receptors at the high nanomolar concentrations (Ki = 76.7 ± 5.8 nm and 12.1 ± 2.3 nm, respectively). Both, HU-446 and HU-465, at 5 and 10 μm (but not at 0.1 and 1 μm), inhibited the MOG35-55-induced proliferation of autoreactive T(MOG) cells via CB1/CB2 receptor independent mechanisms. Moreover, both HU-446 and HU-465, at 5 and 10 μm, inhibited the release of IL-17, a key autoimmune cytokine, from MOG35-55-stimulated T(MOG) cells. These results suggest that HU-446 and HU-465 have anti-inflammatory potential in inflammatory and autoimmune diseases.
authors.affiliation: The Dr Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kozela
authors.affiliation: Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
authors.forename: Christeene
authors.initials: C
authors.lastname: Haj
authors.affiliation: Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
authors.forename: Lumir
authors.initials: L
authors.lastname: Hanuš
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, 844102, Bihar 844102, India.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Chourasia
authors.affiliation: Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
authors.forename: Avital
authors.initials: A
authors.lastname: Shurki
authors.affiliation: The Dr Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
authors.forename: Ana
authors.initials: A
authors.lastname: Juknat
authors.affiliation: Neurobiology Department, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Nathali
authors.initials: N
authors.lastname: Kaushansky
authors.affiliation: Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Mechoulam
authors.affiliation: The Dr Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.|Neurobiology Department, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Vogel
mesh_terms: D000818:Animals; D002185:Cannabidiol / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D008213:Lymphocyte Activation / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D002185:Cannabidiol
keywords: HU-446; HU-465; IL-17; Th17; cannabidiol derivatives; encephalitogenic T cells