Repurposing of omeprazole for oligodendrocyte differentiation and remyelination

Brain Res. 2019 May 1;1710:33-42. doi: 10.1016/j.brainres.2018.12.037. Epub 2018 Dec 24.

Abstract

The efficiency of remyelination determines the degree of neuronal recovery and clinical amelioration of patients with Multiple Sclerosis (MS). However, the lack of drugs facilitating myelin regeneration represents a currently unmet medical need. Herein we utilized public microarray results from the GEO database and analyzed them using Connectivity-Map, which is a database connecting diseases, genes and drugs. Through this screening, we identified Omeprazole as a potential, applicable pro-remyelinating drug candidate. Incubation of isolated primary oligodendrocyte precursor cells with omeprazole in vitro significantly promoted the differentiation and maturation of oligodendrocyte precursor cells. Employing different inhibitors of the MAPK pathway, we found that the phosphorylation of ERK1/2 and p38 MAPK is required for this effect of omeprazole. The cuprizone-induced demyelination mouse model was applied to examine the pro-remyelinating effect of omeprazole in vivo. Omeprazole treatment (10 mg/kg) for 2 weeks significantly improved the impaired motor coordinative function of demyelinated mice, increased the expression of myelin basic protein (MBP) and up-regulated the expression of genes related to remyelination. The proportion of myelinated axons was also increased after omeprazole treatment as revealed by transmission electron microscopy. Our data demonstrate that omeprazole is a promising drug candidate for remyelination in MS.

Keywords: Connectivity map; Multiple Sclerosis; Oligodendrocyte; Omeprazole; Remyelination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Cell Differentiation / drug effects
  • Cuprizone / pharmacology
  • Demyelinating Diseases / chemically induced
  • Drug Repositioning / methods
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myelin Sheath / metabolism
  • Neurogenesis / drug effects
  • Oligodendroglia / drug effects*
  • Omeprazole / pharmacology*
  • Primary Cell Culture
  • Rats
  • Remyelination / drug effects
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cuprizone
  • p38 Mitogen-Activated Protein Kinases
  • Omeprazole