Mathias Gelderblom1, Nico Melzer1, Benjamin Schattling1, Eva Göb1, Gordon Hicking1, Priyadharshini Arunachalam1, Stefan Bittner1, Friederike Ufer1, Alexander M Herrmann1, Christian Bernreuther1, Markus Glatzel1, Christian Gerloff1, Christoph Kleinschnitz1, Sven G Meuth1, Manuel A Friese2, Tim Magnus2. 1. 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.). 2. 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.
Abstract
BACKGROUND AND PURPOSE: 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.
BACKGROUND AND PURPOSE: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 murineischemic 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-deficientmice. 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: Robert M Dietz; Ivelisse Cruz-Torres; James E Orfila; Olivia P Patsos; Kaori Shimizu; Nicholas Chalmers; Guiying Deng; Erika Tiemeier; Nidia Quillinan; Paco S Herson Journal: Transl Stroke Res Date: 2019-06-28 Impact factor: 6.829