title: Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model.
abstract: Although there is growing evidence for a role of excess intracellular cations, particularly calcium ions, in neuronal and glial cell injury in multiple sclerosis, as well as in non-inflammatory neurological conditions, the molecular mechanisms involved are not fully determined. We previously showed that the acid-sensing ion channel 1 which, when activated under the acidotic tissue conditions found in inflammatory lesions opens to allow influx of sodium and calcium ions, contributes to axonal injury in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. However, the extent and cellular distribution of acid-sensing ion channel 1 expression in neurons and glia in inflammatory lesions is unknown and, crucially, acid-sensing ion channel 1 expression has not been determined in multiple sclerosis lesions. Here we studied acute and chronic experimental autoimmune encephalomyelitis and multiple sclerosis spinal cord and optic nerve tissues to describe in detail the distribution of acid-sensing ion channel 1 and its relationship with neuronal and glial damage. We also tested the effects of amiloride treatment on tissue damage in the mouse models. We found that acid-sensing ion channel 1 was upregulated in axons and oligodendrocytes within lesions from mice with acute experimental autoimmune encephalomyelitis and from patients with active multiple sclerosis. The expression of acid-sensing ion channel 1 was associated with axonal damage as indicated by co-localization with the axonal injury marker beta amyloid precursor protein. Moreover, blocking acid-sensing ion channel 1 with amiloride protected both myelin and neurons from damage in the acute model, and when given either at disease onset or, more clinically relevant, at first relapse, ameliorated disability in mice with chronic-relapsing experimental autoimmune encephalomyelitis. Together these findings suggest that blockade of acid-sensing ion channel 1 has the potential to provide both neuro- and myelo-protective benefits in multiple sclerosis.
authors.affiliation: Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Vergo
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Craner
authors.forename: Ruth
authors.initials: R
authors.lastname: Etzensperger
authors.forename: Kathrine
authors.initials: K
authors.lastname: Attfield
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
authors.forename: Jia
authors.initials: J
authors.lastname: Newcombe
authors.forename: Margaret
authors.initials: M
authors.lastname: Esiri
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
mesh_terms: D062565:Acid Sensing Ion Channels; D000368:Aged; D000584:Amiloride / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018929:Cell Culture Techniques; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009836:Oligodendroglia / Q000378:metabolism; D009900:Optic Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015222:Sodium Channels / Q000096:biosynthesis*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
chemical_list: D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D015222:Sodium Channels; D000584:Amiloride