RT Journal Article T1 Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: implications for multiple sclerosis therapy. A1 Navarrete, Carmen A1 Carrillo-Salinas, Francisco A1 Palomares, Belen A1 Mecha, Miriam A1 Jimenez-Jimenez, Carla A1 Mestre, Leyre A1 Feliu, Ana A1 Bellido, Maria L A1 Fiebich, Bernd L A1 Appendino, Giovanni A1 Calzado, Marco A A1 Guaza, Carmen A1 Muñoz, Eduardo K1 Arginase 1 K1 Cannabinoids K1 EPO K1 HIF-1α K1 Multiple sclerosis K1 PHDs K1 VEGF AB Multiple sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes variously dominant in different stages of the disease. Thus, immunosuppression is the goal standard for the inflammatory stage, and novel remyelination therapies are pursued to restore lost function. Cannabinoids such as 9Δ-THC and CBD are multi-target compounds already introduced in the clinical practice for multiple sclerosis (MS). Semisynthetic cannabinoids are designed to improve bioactivities and druggability of their natural precursors. VCE-004.8, an aminoquinone derivative of cannabidiol (CBD), is a dual PPARγ and CB2 agonist with potent anti-inflammatory activity. Activation of the hypoxia-inducible factor (HIF) can have a beneficial role in MS by modulating the immune response and favoring neuroprotection and axonal regeneration. We investigated the effects of VCE-004.8 on the HIF pathway in different cell types. The effect of VCE-004.8 on macrophage polarization and arginase 1 expression was analyzed in RAW264.7 and BV2 cells. COX-2 expression and PGE2 synthesis induced by lipopolysaccharide (LPS) was studied in primary microglia cultures. The efficacy of VCE-004.8 in vivo was evaluated in two murine models of MS such as experimental autoimmune encephalomyelitis (EAE) and Theiler's virus-induced encephalopathy (TMEV). Herein, we provide evidence that VCE-004.8 stabilizes HIF-1α and HIF-2α and activates the HIF pathway in human microvascular endothelial cells, oligodendrocytes, and microglia cells. The stabilization of HIF-1α is produced by the inhibition of the prolyl-4-hydrolase activity of PHD1 and PDH2. VCE-004.8 upregulates the expression of HIF-dependent genes such as erythropoietin and VEGFA, induces angiogenesis, and enhances migration of oligodendrocytes. Moreover, VCE-004.8 blunts IL-17-induced M1 polarization, inhibits LPS-induced COX-2 expression and PGE2 synthesis, and induces expression of arginase 1 in macrophages and microglia. In vivo experiments showed efficacy of VCE-004.8 in EAE and TMEV. Histopathological analysis revealed that VCE-004.8 treatments prevented demyelination, axonal damage, and immune cells infiltration. In addition, VCE-004.8 downregulated the expression of several genes closely associated with MS physiopathology, including those underlying the production of chemokines, cytokines, and adhesion molecules. This study provides new significant insights about the potential role of VCE-004.8 for MS treatment by ameliorating neuroinflammation and demyelination. PB BioMed Central YR 2018 FD 2018-02-21 LK http://hdl.handle.net/10668/12198 UL http://hdl.handle.net/10668/12198 LA en NO Navarrete C, Carrillo-Salinas F, Palomares B, Mecha M, Jiménez-Jiménez C, Mestre L, et al. Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: implications for multiple sclerosis therapy. J Neuroinflammation. 2018 Mar 1;15(1):64 DS RISalud RD Feb 14, 2025