title: Transient receptor potential melastatin subfamily member 2 cation channel regulates detrimental immune cell invasion in ischemic stroke.
abstract: OBJECTIVE
  Brain injury during stroke results in oxidative stress and the release of factors that include extracellular Ca(2+), hydrogen peroxide, adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate. These alterations of the extracellular milieu change the activity of transient receptor potential melastatin subfamily member 2 (TRPM2), a nonselective cation channel expressed in the central nervous system and the immune system. Our goal was to evaluate the contribution of TRPM2 to the tissue damage after stroke.
  
  
  METHODS
  In accordance with current quality guidelines, we independently characterized Trpm2 in a murine ischemic stroke model in 2 different laboratories.
  
  
  RESULTS
  Gene deficiency of Trpm2 resulted in significantly improved neurological outcome and decreased infarct size. Besides an already known moderate neuroprotective effect of Trpm2 deficiency in vitro, ischemic brain invasion by neutrophils and macrophages was particularly reduced in Trpm2-deficient mice. Bone marrow chimeric mice revealed that Trpm2 deficiency in the peripheral immune system is responsible for the protective phenotype. Furthermore, experiments with mixed bone marrow chimeras demonstrated that Trpm2 is essential for the migration of neutrophils and, to a lesser extent, also of macrophages into ischemic hemispheres. Notably, the pharmacological TRPM2 inhibitor, N-(p-amylcinnamoyl)anthranilic acid, was equally protective in the stroke model.
  
  
  CONCLUSIONS
  Although a neuroprotective effect of TRPM2 in vitro is well known, we can show for the first time that the detrimental role of TRPM2 in stroke primarily depends on its role in activating peripheral immune cells. Targeting TRPM2 systemically represents a promising therapeutic approach for ischemic stroke.
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Mathias
authors.initials: M
authors.lastname: Gelderblom
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Nico
authors.initials: N
authors.lastname: Melzer
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schattling
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Eva
authors.initials: E
authors.lastname: Göb
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Gordon
authors.initials: G
authors.lastname: Hicking
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Priyadharshini
authors.initials: P
authors.lastname: Arunachalam
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Friederike
authors.initials: F
authors.lastname: Ufer
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Herrmann
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Christian
authors.initials: C
authors.lastname: Bernreuther
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Christian
authors.initials: C
authors.lastname: Gerloff
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.).
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.). t.magnus@uke.de manuel.friese@zmnh.uni-hamburg.de.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
authors.affiliation: From the Department of Neurology (M. Gelderblom, P.A., C.G., T.M.), Institute of Neuroimmunology and Multiple Sclerosis (B.S., F.U., M.A.F.), and Institute of Neuropathology (C.B., M. Glatzel), University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Neurology, University of Muenster, Muenster, Germany (N.M., G.H., S.B., A.M.H., S.G.M.); and Department of Neurology, University Clinics Wuerzburg, Wuerzburg, Germany (E.G., C.K.). t.magnus@uke.de manuel.friese@zmnh.uni-hamburg.de.
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D007111:Immunity, Cellular / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D011897:Random Allocation; D020521:Stroke / Q000276:immunology* / Q000473:pathology; D050053:TRPM Cation Channels / Q000502:physiology*
chemical_list: D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse
keywords: inflammation; ion channels; neutrophils; stroke