title: Myeloperoxidase propagates damage and is a potential therapeutic target for subacute stroke.
abstract: Few effective treatment options exist for stroke beyond the hyperacute period. Radical generation and myeloperoxidase (MPO) have been implicated in stroke. We investigated whether pharmacologic reduction or gene deletion of this highly oxidative enzyme reduces infarct propagation and improves outcome in the transient middle cerebral artery occlusion mouse model (MCAO). Mice were treated with 4-aminobenzoic acid hydrazide (ABAH), a specific irreversible MPO inhibitor. Three treatment regimens were used: (1) daily throughout the 21-day observational period, (2) during the acute stage (first 24 hours), or (3) during the subacute stage (daily starting on day 2). We found elevated MPO activity in ipsilateral brain 3 to 21 days after ischemia. 4-Aminobenzoic acid hydrazide reduced enzyme activity by 30% to 40% and final lesion volume by 60% (P<0.01). The MPO-knockout (KO) mice subjected to MCAO also showed a similar reduction in the final lesion volume (P<0.01). The ABAH treatment or MPO-KO mice also improved neurobehavioral outcome (P<0.001) and survival (P=0.01), but ABAH had no additional beneficial effects in MPO-KO mice, confirming specificity of ABAH. Interestingly, inhibiting MPO activity during the subacute stage recapitulated most of the therapeutic benefit of continuous MPO inhibition, suggesting that MPO-targeted therapies could be useful when given after 24 hours of stroke onset.
authors.affiliation: 1] Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Reza
authors.initials: R
authors.lastname: Forghani
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hyeon Ju
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wojtkiewicz
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lionel
authors.initials: L
authors.lastname: Bure
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hayase
authors.affiliation: Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 1] Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moskowitz
authors.affiliation: 1] Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Division of Neuroradiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism*; D020521:Stroke / Q000201:enzymology* / Q000473:pathology*
chemical_list: D004791:Enzyme Inhibitors; D009195:Peroxidase