The vincamine derivative vindeburnol provides benefit in a mouse model of multiple sclerosis: Effects on the Locus coerules

Paul E. Polak, Sergey Kalinin, Davib Braun, Anthony Sharp, Shao X. Lin, Douglas L. Feinstein

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish
Pages (from-to)206-216
Number of pages11
JournalJournal of Neurochemistry
Volume121
Issue number2
DOIs
StatePublished - Apr 2012

Keywords

  • Experimental autoimmune encephalomyelitis
  • Glial cells
  • Locus coeruleus
  • Noradrenaline
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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