title: TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis.
abstract: In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the antidiabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4(-/-) mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.
authors.affiliation: Forschergruppe Neuroimmunologie, Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schattling
authors.forename: Karin
authors.initials: K
authors.lastname: Steinbach
authors.forename: Edda
authors.initials: E
authors.lastname: Thies
authors.forename: Martin
authors.initials: M
authors.lastname: Kruse
authors.forename: Aurélie
authors.initials: A
authors.lastname: Menigoz
authors.forename: Friederike
authors.initials: F
authors.lastname: Ufer
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Olaf
authors.initials: O
authors.lastname: Pongs
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.forename: Marc
authors.initials: M
authors.lastname: Freichel
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D050053:TRPM Cation Channels; C437888:TRPM4 protein, human; D005905:Glyburide