Hypoxia mimetic activity of VCE-004.8, a cannabidiol quinone derivative: implications for multiple sclerosis therapy

• DOI: 10.1186/s12974-018-1103-y
• Publication Date: 2018-03-01T02:55:38Z
• Authors: Carmen Navarrete; Francisco Carrill...; Belén Palomares; Miriam Mecha; Carla Jiménez-Jim...; Leyre Mestre; Ana Feliú; Maria L. Bellido; Bernd L. Fiebich; Giovanni Appendino; Marco A. Calzado; Carmen Guaza; Eduardo Muñoz
• Keywords: Andrographolide

Multiple sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes variously dominant in different stages the disease. Thus, immunosuppression goal standard for stage, novel remyelination therapies are pursued to restore lost function. Cannabinoids such as 9Δ-THC CBD multi-target compounds already introduced clinical practice multiple (MS). Semisynthetic cannabinoids designed improve bioactivities druggability their natural precursors. VCE-004.8, an aminoquinone derivative cannabidiol (CBD), dual PPARγ CB2 agonist with potent anti-inflammatory activity. Activation hypoxia-inducible factor (HIF) can have beneficial role MS modulating immune response favoring neuroprotection axonal regeneration.We investigated effects VCE-004.8 on HIF pathway cell types. The effect macrophage polarization arginase 1 expression was analyzed RAW264.7 BV2 cells. COX-2 PGE2 synthesis induced lipopolysaccharide (LPS) studied primary microglia cultures. efficacy vivo evaluated two murine models experimental autoimmune encephalomyelitis (EAE) Theiler's virus-induced encephalopathy (TMEV).Herein, we provide evidence that stabilizes HIF-1α HIF-2α activates human microvascular endothelial cells, oligodendrocytes, stabilization produced inhibition prolyl-4-hydrolase activity PHD1 PDH2. upregulates HIF-dependent genes erythropoietin VEGFA, induces angiogenesis, enhances migration oligodendrocytes. Moreover, blunts IL-17-induced M1 polarization, inhibits LPS-induced synthesis, macrophages microglia. In experiments showed EAE TMEV. Histopathological analysis revealed treatments prevented demyelination, damage, cells infiltration. addition, downregulated several closely associated physiopathology, including those underlying production chemokines, cytokines, adhesion molecules.This study provides new significant insights about potential treatment ameliorating neuroinflammation demyelination.