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.
authors.affiliation: Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Eleuteri
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato 09042, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Olla
authors.affiliation: Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Veroni
authors.affiliation: Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Umeton
authors.affiliation: Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Mechelli
authors.affiliation: Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Romano
authors.affiliation: Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Buscarinu
authors.affiliation: Department of Medical Science, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ferrari
authors.affiliation: Department of Medical Science, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Calò
authors.affiliation: Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ristori
authors.affiliation: Center for Experimental Neurological Therapies, Sant'Andrea Hospital, Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Italy.|IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, 86077 Pozzilli, IS, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Salvetti
authors.affiliation: Department of Neuroscience, Istituto Superiore di Sanità, 00161 Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Agresti
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D051379:Mice; D009186:Myelin Sheath / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D000073637:Oligodendrocyte Precursor Cells / Q000187:drug effects* / Q000378:metabolism; D000074586:Remyelination
chemical_list: D018696:Neuroprotective Agents