title: Locus coeruleus damage and noradrenaline reductions in multiple sclerosis and experimental autoimmune encephalomyelitis.
abstract: The endogenous neurotransmitter noradrenaline exerts anti-inflammatory and neuroprotective effects in vitro and in vivo. Several studies report that noradrenaline levels are altered in the central nervous system of patients with multiple sclerosis and rodents with experimental autoimmune encephalomyelitis, which could contribute to pathology. Since the major source of noradrenaline are neurons in the locus coeruleus, we hypothesized that alterations in noradrenaline levels are a consequence of stress or damage to locus coeruleus neurons. In C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide 35-55 to develop chronic disease, cortical and spinal cord levels of noradrenaline were significantly reduced versus control mice. Immunohistochemical staining revealed increased astrocyte activation in the ventral portion of the locus coeruleus in immunized mice. The immunized mice showed neuronal damage in the locus coeruleus detected by a reduction of average cell size of tyrosine hydroxylase stained neurons. Analysis of the locus coeruleus of multiple sclerosis and control brains showed a significant increase in astrocyte activation, a reduction in noradrenaline levels, and neuronal stress indicated by hypertrophy of tyrosine hydroxylase stained cell bodies. However, the magnitude of these changes was not correlated with extent of demyelination or of cellular infiltrates. Together these findings demonstrate the presence of inflammation and neuronal stress in multiple sclerosis as well as in experimental autoimmune encephalomyelitis. Since reduced noradrenaline levels could be permissive for increased inflammation and neuronal damage, these results suggest that methods to raise noradrenaline levels or increase locus coeruleus function may be of benefit in treating multiple sclerosis.
authors.affiliation: Department of Anaesthesiology, University of Illinois at Chicago, Jesse Brown Medical Centre, Chicago, IL 60612, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Polak
authors.forename: Sergey
authors.initials: S
authors.lastname: Kalinin
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D047208:Eosinophil-Derived Neurotoxin / Q000235:genetics / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins / Q000009:adverse effects; D006801:Humans; D008125:Locus Coeruleus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000378:metabolism*; D010446:Peptide Fragments / Q000009:adverse effects; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D012333:RNA, Messenger; C445081:myelin oligodendrocyte glycoprotein (35-55); D014446:Tyrosine 3-Monooxygenase; C479821:Ear2 protein, mouse; D047208:Eosinophil-Derived Neurotoxin; D009638:Norepinephrine