title: Cholecalciferol (vitamin D₃) improves myelination and recovery after nerve injury.
abstract: Previously, we demonstrated i) that ergocalciferol (vitamin D2) increases axon diameter and potentiates nerve regeneration in a rat model of transected peripheral nerve and ii) that cholecalciferol (vitamin D3) improves breathing and hyper-reflexia in a rat model of paraplegia. However, before bringing this molecule to the clinic, it was of prime importance i) to assess which form - ergocalciferol versus cholecalciferol - and which dose were the most efficient and ii) to identify the molecular pathways activated by this pleiotropic molecule. The rat left peroneal nerve was cut out on a length of 10 mm and autografted in an inverted position. Animals were treated with either cholecalciferol or ergocalciferol, at the dose of 100 or 500 IU/kg/day, or excipient (Vehicle), and compared to unlesioned rats (Control). Functional recovery of hindlimb was measured weekly, during 12 weeks, using the peroneal functional index. Ventilatory, motor and sensitive responses of the regenerated axons were recorded and histological analysis was performed. In parallel, to identify the genes regulated by vitamin D in dorsal root ganglia and/or Schwann cells, we performed an in vitro transcriptome study. We observed that cholecalciferol is more efficient than ergocalciferol and, when delivered at a high dose (500 IU/kg/day), cholecalciferol induces a significant locomotor and electrophysiological recovery. We also demonstrated that cholecalciferol increases i) the number of preserved or newly formed axons in the proximal end, ii) the mean axon diameter in the distal end, and iii) neurite myelination in both distal and proximal ends. Finally, we found a modified expression of several genes involved in axogenesis and myelination, after 24 hours of vitamin supplementation. Our study is the first to demonstrate that vitamin D acts on myelination via the activation of several myelin-associated genes. It paves the way for future randomised controlled clinical trials for peripheral nerve or spinal cord repair.
authors.affiliation: Aix Marseille Université, CNRS, NICN UMR 7259, Marseille, France.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Chabas
authors.forename: Delphine
authors.initials: D
authors.lastname: Stephan
authors.forename: Tanguy
authors.initials: T
authors.lastname: Marqueste
authors.forename: Stephane
authors.initials: S
authors.lastname: Garcia
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Lavaut
authors.forename: Catherine
authors.initials: C
authors.lastname: Nguyen
authors.forename: Regis
authors.initials: R
authors.lastname: Legre
authors.forename: Michel
authors.initials: M
authors.lastname: Khrestchatisky
authors.forename: Patrick
authors.initials: P
authors.lastname: Decherchi
authors.forename: Francois
authors.initials: F
authors.lastname: Feron
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002762:Cholecalciferol / Q000008:administration & dosage / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000187:drug effects; D009186:Myelin Sheath / Q000187:drug effects*; D009416:Nerve Regeneration / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009929:Organ Size; D059348:Peripheral Nerve Injuries / Q000235:genetics / Q000378:metabolism / Q000534:rehabilitation*; D010543:Peroneal Nerve / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D002762:Cholecalciferol