Pharmacogenomic screening identifies and repurposes leucovorin and dyclonine as pro-oligodendrogenic compounds in brain repair

Jean-Baptiste Huré, Louis Foucault, Litsa Maria Ghayad, Corentine Marie, Nicolas Vachoud, Lucas Baudouin, Rihab Azmani, Natalija Ivljanin, Alvaro Arevalo-Nuevo, Morgane Pigache, Lamia Bouslama-Oueghlani, Julie-Anne Chemelle, Marie-Aimée Dronne, Raphaël Terreux, Bassem Hassan, François Gueyffier, Olivier Raineteau () and Carlos Parras ()
Additional contact information
Jean-Baptiste Huré: Hôpital Pitié-Salpêtrière
Louis Foucault: Stem Cell and Brain Research Institute U1208
Litsa Maria Ghayad: Hôpital Pitié-Salpêtrière
Corentine Marie: Hôpital Pitié-Salpêtrière
Nicolas Vachoud: Stem Cell and Brain Research Institute U1208
Lucas Baudouin: Hôpital Pitié-Salpêtrière
Rihab Azmani: Stem Cell and Brain Research Institute U1208
Natalija Ivljanin: Hôpital Pitié-Salpêtrière
Alvaro Arevalo-Nuevo: Hôpital Pitié-Salpêtrière
Morgane Pigache: Hôpital Pitié-Salpêtrière
Lamia Bouslama-Oueghlani: Hôpital Pitié-Salpêtrière
Julie-Anne Chemelle: UMR5305
Marie-Aimée Dronne: CNRS
Raphaël Terreux: UMR5305
Bassem Hassan: Hôpital Pitié-Salpêtrière
François Gueyffier: CNRS
Olivier Raineteau: Stem Cell and Brain Research Institute U1208
Carlos Parras: Hôpital Pitié-Salpêtrière

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: Abstract Oligodendrocytes are critical for CNS myelin formation and are involved in preterm-birth brain injury (PBI) and multiple sclerosis (MS), both of which lack effective treatments. We present a pharmacogenomic approach that identifies compounds with potent pro-oligodendrogenic activity, selected through a scoring strategy (OligoScore) based on their modulation of oligodendrogenic and (re)myelination-related transcriptional programs. Through in vitro neural and oligodendrocyte progenitor cell (OPC) cultures, ex vivo cerebellar explants, and in vivo mouse models of PBI and MS, we identify FDA-approved leucovorin and dyclonine as promising candidates. In a neonatal chronic hypoxia mouse model mimicking PBI, both compounds promote neural progenitor cell proliferation and oligodendroglial fate acquisition, with leucovorin further enhancing differentiation. In an adult MS model of focal de/remyelination, they improve lesion repair by promoting OPC differentiation while preserving the OPC pool. Additionally, they shift microglia from a pro-inflammatory to a pro-regenerative profile and enhance myelin debris clearance. These findings support the repurposing of leucovorin and dyclonine for clinical trials targeting myelin disorders, offering potential therapeutic avenues for PBI and MS.

Date: 2024
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DOI: 10.1038/s41467-024-54003-9

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