title: Myeloperoxidase Inhibition Increases Neurogenesis after Ischemic Stroke.
abstract: The relationship between inflammation and neurogenesis in stroke is currently not well understood. Focal ischemia enhances cell proliferation and neurogenesis in the neurogenic regions, including the subventricular zone (SVZ), dentate gyrus, as well as the non-neurogenic striatum, and cortex in the ischemic hemisphere. Myeloperoxidase (MPO) is a potent oxidizing enzyme secreted during inflammation by activated leukocytes, and its enzymatic activity is highly elevated after stroke. In this study, we investigated whether the inhibition of MPO activity by a specific irreversible inhibitor, 4-aminobenzoic acid hydrazide (ABAH) (MPO-/-mice) can increase neurogenesis after transient middle cerebral artery occlusion in mice. ABAH administration increased the number of proliferating bromodeoxyuridine (BrdU)-positive cells expressing markers for neural stems cells, astrocytes, neuroprogenitor cells (Nestin), and neuroblasts (doublecortin) in the ischemic SVZ, anterior SVZ, striatum, and cortex. MPO inhibition also increased levels of brain-derived neurotrophic factor, phosphorylation of cAMP response element-binding protein (Ser133), acetylated H3, and NeuN to promote neurogenesis in the ischemic SVZ. ABAH treatment also increased chemokine CXC receptor 4 expression in the ischemic SVZ. MPO-deficient mice treated with vehicle or ABAH both showed similar effects on the number of BrdU+cells in the ischemic hemisphere, demonstrating that ABAH is specific to MPO. Taken together, our results underscore a detrimental role of MPO activity to postischemia neurogenesis and that a strategy to inhibit MPO activity can increase cell proliferation and improve neurogenesis after ischemic stroke.
authors.affiliation: Center for Systems Biology and Institute for Innovation in Imaging (H.K., J.Y.L., J.W.C), and Neuroscience Center (Y. Wei, Y. Wu, Y.Z., M.A.M.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: HyeonJu
authors.initials: H
authors.lastname: Kim
authors.affiliation: Center for Systems Biology and Institute for Innovation in Imaging (H.K., J.Y.L., J.W.C), and Neuroscience Center (Y. Wei, Y. Wu, Y.Z., M.A.M.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Center for Systems Biology and Institute for Innovation in Imaging (H.K., J.Y.L., J.W.C), and Neuroscience Center (Y. Wei, Y. Wu, Y.Z., M.A.M.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ji Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Center for Systems Biology and Institute for Innovation in Imaging (H.K., J.Y.L., J.W.C), and Neuroscience Center (Y. Wei, Y. Wu, Y.Z., M.A.M.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Center for Systems Biology and Institute for Innovation in Imaging (H.K., J.Y.L., J.W.C), and Neuroscience Center (Y. Wei, Y. Wu, Y.Z., M.A.M.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Center for Systems Biology and Institute for Innovation in Imaging (H.K., J.Y.L., J.W.C), and Neuroscience Center (Y. Wei, Y. Wu, Y.Z., M.A.M.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moskowitz
authors.affiliation: Center for Systems Biology and Institute for Innovation in Imaging (H.K., J.Y.L., J.W.C), and Neuroscience Center (Y. Wei, Y. Wu, Y.Z., M.A.M.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Jwchen@mgh.harvard.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology*; D000107:Acetylation / Q000187:drug effects; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D020547:Lateral Ventricles / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009687:Nuclear Proteins / Q000378:metabolism; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D019718:Receptors, CXCR4 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000150:complications* / Q000473:pathology* / Q000503:physiopathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C514936:CXCR4 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006657:Histones; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D019718:Receptors, CXCR4; D009195:Peroxidase; D020780:Matrix Metalloproteinase 9; D010129:4-Aminobenzoic Acid