title: Anti-muscarinic adjunct therapy accelerates functional human oligodendrocyte repair.
abstract: Therapeutic repair of myelin disorders may be limited by the relatively slow rate of human oligodendrocyte differentiation. To identify appropriate pharmacological targets with which to accelerate differentiation of human oligodendrocyte progenitors (hOPCs) directly, we used CD140a/O4-based FACS of human forebrain and microarray to hOPC-specific receptors. Among these, we identified CHRM3, a M3R muscarinic acetylcholine receptor, as being restricted to oligodendrocyte-biased CD140a(+)O4(+) cells. Muscarinic agonist treatment of hOPCs resulted in a specific and dose-dependent blockade of oligodendrocyte commitment. Conversely, when hOPCs were cocultured with human neurons, M3R antagonist treatment stimulated oligodendrocytic differentiation. Systemic treatment with solifenacin, an FDA-approved muscarinic receptor antagonist, increased oligodendrocyte differentiation of transplanted hOPCs in hypomyelinated shiverer/rag2 brain. Importantly, solifenacin treatment of engrafted animals reduced auditory brainstem response interpeak latency, indicative of increased conduction velocity and thereby enhanced functional repair. Therefore, solifenacin and other selective muscarinic antagonists represent new adjunct approaches to accelerate repair by engrafted human progenitors.
authors.affiliation: Neuroscience Program.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Abiraman
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Suyog U
authors.initials: SU
authors.lastname: Pol
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: O'Bara
authors.affiliation: School of Medicine and Biomedical Sciences, Center for Hearing and Deafness, University at Buffalo, Buffalo, New York 14214.
authors.forename: Guang-Di
authors.initials: GD
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Zainab M
authors.initials: ZM
authors.lastname: Khaku
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: David
authors.initials: D
authors.lastname: Thorn
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Bansi H
authors.initials: BH
authors.lastname: Vedia
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Ezinne C
authors.initials: EC
authors.lastname: Ekwegbalu
authors.affiliation: Department of Pharmacology and Toxicology, and.
authors.forename: Jun-Xu
authors.initials: JX
authors.lastname: Li
authors.affiliation: School of Medicine and Biomedical Sciences, Center for Hearing and Deafness, University at Buffalo, Buffalo, New York 14214.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Salvi
authors.affiliation: Neuroscience Program, Department of Pharmacology and Toxicology, and fjsim@buffalo.edu.
authors.forename: Fraser J
authors.initials: FJ
authors.lastname: Sim
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D016057:Evoked Potentials, Auditory, Brain Stem; D005260:Female; D053686:Fetal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis; D019081:O Antigens / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology; D011812:Quinuclidines / Q000494:pharmacology*; D043587:Receptor, Muscarinic M3; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
chemical_list: C000595896:CHRM3 protein, human; D004268:DNA-Binding Proteins; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D019081:O Antigens; D011812:Quinuclidines; C499308:Rag2 protein, mouse; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D044005:Tetrahydroisoquinolines; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000069464:Solifenacin Succinate
keywords: glia; human; microarray; oligodendrocyte