A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

C. Eleuteri, S. Olla, C. Veroni, R. Umeton, R. Mechelli, S. Romano, M. C. Buscarinu, F. Ferrari, G. Calò, G. Ristori, M. Salvetti, C. Agresti

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

Original languageEnglish
Article number45780
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - Apr 7 2017

Fingerprint

Preclinical Drug Evaluations
Oligodendroglia
Clinical Trials
Pharmaceutical Preparations
Lovastatin
Amyotrophic Lateral Sclerosis
Neuroprotective Agents
United States Food and Drug Administration
Myelin Sheath
Biological Products
Neuroglia
Multiple Sclerosis
Japan
Stroke
phenylmethylpyrazolone

Keywords

  • Multiple sclerosis (MS)
  • Drug Repositioning
  • Remyelination
  • Oligodendrocyte progenitors
  • edaravone

ASJC Scopus subject areas

  • General

Cite this

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials. / Eleuteri, C.; Olla, S.; Veroni, C.; Umeton, R.; Mechelli, R.; Romano, S.; Buscarinu, M. C.; Ferrari, F.; Calò, G.; Ristori, G.; Salvetti, M.; Agresti, C.

In: Scientific Reports, Vol. 7, 45780, 07.04.2017.

Research output: Contribution to journalArticle

Eleuteri, C, Olla, S, Veroni, C, Umeton, R, Mechelli, R, Romano, S, Buscarinu, MC, Ferrari, F, Calò, G, Ristori, G, Salvetti, M & Agresti, C 2017, 'A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials', Scientific Reports, vol. 7, 45780. https://doi.org/10.1038/srep45780
Eleuteri, C. ; Olla, S. ; Veroni, C. ; Umeton, R. ; Mechelli, R. ; Romano, S. ; Buscarinu, M. C. ; Ferrari, F. ; Calò, G. ; Ristori, G. ; Salvetti, M. ; Agresti, C. / A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials. In: Scientific Reports. 2017 ; Vol. 7.
@article{987ad53fce5743bcb48fc16bac308a95,
title = "A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials",
abstract = "There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.",
keywords = "Multiple sclerosis (MS), Drug Repositioning, Remyelination, Oligodendrocyte progenitors, edaravone",
author = "C. Eleuteri and S. Olla and C. Veroni and R. Umeton and R. Mechelli and S. Romano and Buscarinu, {M. C.} and F. Ferrari and G. Cal{\`o} and G. Ristori and M. Salvetti and C. Agresti",
year = "2017",
month = "4",
day = "7",
doi = "10.1038/srep45780",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

AU - Eleuteri, C.

AU - Olla, S.

AU - Veroni, C.

AU - Umeton, R.

AU - Mechelli, R.

AU - Romano, S.

AU - Buscarinu, M. C.

AU - Ferrari, F.

AU - Calò, G.

AU - Ristori, G.

AU - Salvetti, M.

AU - Agresti, C.

PY - 2017/4/7

Y1 - 2017/4/7

N2 - There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

AB - There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

KW - Multiple sclerosis (MS)

KW - Drug Repositioning

KW - Remyelination

KW - Oligodendrocyte progenitors

KW - edaravone

UR - http://www.scopus.com/inward/record.url?scp=85017234556&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85017234556&partnerID=8YFLogxK

U2 - 10.1038/srep45780

DO - 10.1038/srep45780

M3 - Article

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 45780

ER -