title: Pivotal role of choline metabolites in remyelination.
abstract: Neuroprotective approaches for central nervous system regeneration have not been successful in clinical practice so far and compounds that enhance remyelination are still not available for patients with multiple sclerosis. The objective of this study was to determine potential regenerative effects of the substance cytidine-5'-diphospho (CDP)-choline in two different murine animal models of multiple sclerosis. The effects of exogenously applied CDP-choline were tested in murine myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. In addition, the cuprizone-induced mouse model of de- and remyelination was used to specifically test the hypothesis that CDP-choline directly increases remyelination. We found that CDP-choline ameliorated the disease course of experimental autoimmune encephalomyelitis and exerted beneficial effects on myelin, oligodendrocytes and axons. After cuprizone-induced demyelination, CDP-choline effectively enhanced myelin regeneration and reversed motor coordination deficits. The increased remyelination arose from an increase in the numbers of proliferating oligodendrocyte precursor cells and oligodendrocytes. Further in vitro studies suggest that this process is regulated by protein kinase C. We thus identified a new mechanism to enhance central nervous system remyelination via the choline pathway. Due to its regenerative action combined with an excellent safety profile, CDP-choline could become a promising substance for patients with multiple sclerosis as an add-on therapy.
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Skripuletz
authors.affiliation: 2 Ruhr-University Bochum, International Graduate School of Neuroscience, 44801 Bochum, Germany 3 Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Manzel
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Karoline
authors.initials: K
authors.lastname: Gropengießer
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Schäfer
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gudi
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany 4 Centre for Systems Neuroscience, 30559 Hannover, Germany.
authors.forename: Vikramjeet
authors.initials: V
authors.lastname: Singh
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany 4 Centre for Systems Neuroscience, 30559 Hannover, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Salinas Tejedor
authors.affiliation: 3 Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jörg
authors.affiliation: 3 Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Hammer
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Voss
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Franca
authors.initials: F
authors.lastname: Vulinovic
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Diane
authors.initials: D
authors.lastname: Degen
authors.affiliation: 3 Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wolf
authors.affiliation: 3 Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: De-Hyung
authors.initials: DH
authors.lastname: Lee
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Refik
authors.initials: R
authors.lastname: Pul
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Darius
authors.initials: D
authors.lastname: Moharregh-Khiabani
authors.affiliation: 4 Centre for Systems Neuroscience, 30559 Hannover, Germany 5 Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.affiliation: 6 Department of Neurology, St Josef Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: 3 Department of Neurology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Linker
authors.affiliation: 1 Department of Neurology, Hannover Medical School, 30625 Hannover, Germany 4 Centre for Systems Neuroscience, 30559 Hannover, Germany Stangel.Martin@MH-Hannover.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Stangel
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents; D002794:Choline / Q000378:metabolism*; D003471:Cuprizone; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000187:drug effects*; D058953:Neural Stem Cells / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects; D018697:Nootropic Agents / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D002614:Chelating Agents; D018697:Nootropic Agents; D003566:Cytidine Diphosphate Choline; D003471:Cuprizone; D002794:Choline
keywords: EAE; demyelination; neuroinflammation; oligodendrocyte; remyelination