RT Journal Article
T1 Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis.
A1 Navarrete, Carmen
A1 Garcia-Martin, Adela
A1 Garrido-Rodriguez, Martin
A1 Mestre, Leyre
A1 Feliu, Ana
A1 Guaza, Carmen
A1 Calzado, Marco A
A1 Muñoz, Eduardo
K1 EHP-101
K1 Inflammation
K1 Multiple sclerosis
K1 Remyelination
K1 Transcriptomic
AB Multiple 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 (PPARγ/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.
PB Elsevier
YR 2020
FD 2020-06-20
LK http://hdl.handle.net/10668/15843
UL http://hdl.handle.net/10668/15843
LA en
NO Navarrete C, García-Martin A, Garrido-Rodríguez M, Mestre L, Feliú A, Guaza C, et al. Effects of EHP-101 on inflammation and remyelination in murine models of Multiple sclerosis. Neurobiol Dis. 2020 Sep;143:104994
DS RISalud
RD Apr 8, 2025