title: The vincamine derivative vindeburnol provides benefit in a mouse model of multiple sclerosis: effects on the Locus coeruleus.
abstract: The endogenous neurotransmitter noradrenaline (NA) plays several roles in maintaining brain homeostasis, including exerting anti-inflammatory and neuroprotective effects. The primary source of NA in the CNS are tyrosine hydroxylase (TH)-positive neurons located in the Locus coeruleus (LC) which send projections throughout the brain and spinal cord. We recently demonstrated that dysregulation of the LC:Noradrenergic system occurs in experimental autoimmune encephalomyelitis as well as in MS patients, associated with damage occurring to LC neurons. Vindeburnol, a structural analog of the cerebral vasodilator vincamine, was previously reported to increase TH expression and activity in LC neurons. Female C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide, and treated with vindeburnol at the first appearance of clinical signs. Clinical signs continued to increase for about 1 week, at which point mice in the vehicle group continued to worsen while vindeburnol-treated mice showed improvement. Pro-inflammatory cytokine production from splenic T cells was not reduced by vindeburnol suggesting primarily central actions of treatment. In the cerebellum, vindeburnol decreased astrocyte activation and reduced the number of demyelinated regions. Vindeburnol reduced astrocyte activation in the LC, reduced TH+ neuronal hypertrophy, increased expression of several genes involved in LC survival and maturation, and increased NA levels in the spinal cord. These results suggest that treatments with drugs such as vindeburnol which target LC survival or function could be of benefit in MS patients.
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Polak
authors.forename: Sergey
authors.initials: S
authors.lastname: Kalinin
authors.forename: David
authors.initials: D
authors.lastname: Braun
authors.forename: Anthony
authors.initials: A
authors.lastname: Sharp
authors.forename: Shao X
authors.initials: SX
authors.lastname: Lin
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D008125:Locus Coeruleus / Q000187:drug effects* / Q000503:physiopathology; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D009185:Myelin Proteins / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009457:Neuroglia / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013534:Survival; D013601:T-Lymphocytes / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014749:Vincamine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D016207:Cytokines; D007202:Indicators and Reagents; C571327:Mog protein, mouse; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; D014749:Vincamine; C044616:vindeburnol; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine