Identification of novel myelin repair drugs by modulation of oligodendroglial differentiation competence

Abstract

Background In multiple sclerosis loss of myelin and oligodendrocytes impairs saltatory signal transduction and leads to neuronal loss and functional deficits. Limited capacity of oligodendroglial precursor cells to differentiate into mature cells is the main reason for inefficient myelin repair in the central nervous system. Drug repurposing constitutes a powerful approach for identification of pharmacological compounds promoting this process. Methods A phenotypic compound screening using the subcellular distribution of a potent inhibitor of oligodendroglial cell differentiation, namely p57kip2, as differentiation competence marker was conducted. Hit compounds were validated in terms of their impact on developmental cell differentiation and myelination using both rat and human primary cell cultures and organotypic cerebellar slice cultures, respectively. Their effect on spontaneous remyelination was then investigated following cuprizone-mediated demyelination of the corpus callosum. Findings A number of novel small molecules able to promote oligodendroglial cell differentiation were identified and a subset was found to foster human oligodendrogenesis as well as myelination ex vivo . Among them the steroid danazol and the anthelminthic parbendazole were found to increase myelin repair. Interpretation We provide evidence that early cellular processes involved in differentiation decisions are applicable for the identification of regeneration promoting drugs and we suggest danazol and parbendazole as potent therapeutic candidates for demyelinating diseases. Funding This work was supported by the Jürgen Manchot Foundation, Düsseldorf; Research Commission of the Medical Faculty of Heinrich-Heine-University Düsseldorf; Christiane and Claudia Hempel Foundation; Stifterverband/Novartisstiftung; James and Elisabeth Cloppenburg, Peek and Cloppenburg Düsseldorf Stiftung and International Progressive MS Alliance (BRAVEinMS).

Insights into myelin dysfunction in schizophrenia and bipolar disorder

“…Several recent studies have focused on the effects of commonly prescribed antipsychotic drugs on oligodendrocytes/myelin[ 184 ]. However, testing the effects of novel compounds intended to induce oligodendrogenesis and (re)myelination[ 116 ] in preclinical models of schizophrenia and bipolar disorder could also hold great promise for future research.…”

“…Based on the findings of that work, Katsel et al [ 113 ] suggested that postmitotic oligodendrocytes may abnormally re-enter the cell cycle, while a significantly increased level of NG2 in the putamen of schizophrenia patients suggested that OPCs failed to exit the cell cycle. Dysregulation of p57Kip2 gene expression in schizophrenia patient samples[ 113 ] could also be related to impaired oligodendrocyte maturation, since this protein has been characterized as an oligodendroglial differentiation competence marker[ 114 - 116 ].…”

Progress in the Application of Drugs for the Treatment of Multiple Sclerosis

“…Manousi et al ( Manousi et al, 2021 ) identified some new small molecules that could promote oligodendrocyte differentiation, even in the presence of the oligodendrocyte differentiation inhibitor p57Kip2 and found subsets that could promote human oligodendrocyte genesis and myelin formation in vitro . Among them, danazol and parbendazole promote oligodendrocyte differentiation and myelin repair.…”

Oligodendrocyte Development and Implication in Perinatal White Matter Injury

“…High-throughput screening (HTS) platform allows for the identification of approved compounds for repurposing therapy as well as drug discovery ( Eleuteri et al, 2017 ; Manousi et al, 2021 ). Indeed, screenings for pharmaceutical compounds that promote myelination have revealed several modulators for G protein-coupled receptor (GPCRs) that are major pharmacological targets for myelin-related diseases ( Table 3 ; Mei et al, 2016 ; Mogha et al, 2016 ; Folts et al, 2019 ).…”