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Title

Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis

AuthorsNavarrete, Carmen; García-Martín, A; Garrido-Rodriguez, Martí; Mestre, Leyre ; Feliú, Ana; Guaza, Carmen ; Calzado, Marco A.; Muñoz, Eduardo
KeywordsMultiple sclerosis
EHP-101
Transcriptomic
Inflammation
Remyelination
Issue Date2020
PublisherAcademic Press
CitationNeurobiology of Disease 143: 104994 (2020)
AbstractMultiple Sclerosis (MS) is characterized by a combination of inflammatory and neurodegenerative processes in the spinal cord and the brain. Natural and synthetic cannabinoids such as VCE-004.8 have been studied in preclinical models of MS and represent promising candidates for drug development. VCE-004.8 is a multitarget synthetic cannabidiol (CBD) derivative acting as a dual Peroxisome proliferator-activated receptor-gamma/ Cannabinoid receptor type 2 (PPAR¿/CB2) ligand agonist that also activates the Hypoxia-inducible factor (HIF) pathway. EHP-101 is an oral lipidic formulation of VCE-004.8 that has shown efficacy in several preclinical models of autoimmune, inflammatory, fibrotic, and neurodegenerative diseases. EHP-101 alleviated clinical symptomatology in EAE and transcriptomic analysis demonstrated that EHP-101 prevented the expression of many inflammatory genes closely associated with MS pathophysiology in the spinal cord. EHP-101 normalized the expression of several genes associated with oligodendrocyte function such as Teneurin 4 (Tenm4) and Gap junction gamma-3 (Gjc3) that were downregulated in EAE. EHP-101 treatment prevented microglia activation and demyelination in both the spinal cord and the brain. Moreover, EAE was associated with a loss in the expression of Oligodendrocyte transcription factor 2 (Olig2) in the corpus callosum, a marker for oligodendrocyte differentiation, which was restored by EHP-101 treatment. In addition, EHP-101 enhanced the expression of glutathione S-transferase pi (GSTpi), a marker for mature oligodendrocytes in the brain. We also found that a diet containing 0.2% cuprizone for six weeks induced a clear loss of myelin in the brain measured by Cryomyelin staining and Myelin basic protein (MBP) expression. Moreover, EHP-101 also prevented cuprizone induced microglial activation, astrogliosis and reduced axonal damage. Our results provide evidence that EHP- 101 showed potent anti-inflammatory activity, prevented demyelination, and enhanced remyelination. Therefore, EHP-101 represents a promising drug candidate for the potential treatment of different forms of MS.
Publisher version (URL)http://dx.doi.org/10.1016/j.nbd.2020.104994
URIhttp://hdl.handle.net/10261/219645
Identifiersdoi: 10.1016/j.nbd.2020.104994
issn: 1095-953X
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