title: Inhibition of myeloperoxidase oxidant production by N-acetyl lysyltyrosylcysteine amide reduces brain damage in a murine model of stroke.
abstract: Oxidative stress plays an important and causal role in the mechanisms by which ischemia/reperfusion (I/R) injury increases brain damage after stroke. Accordingly, reducing oxidative stress has been proposed as a therapeutic strategy for limiting damage in the brain after stroke. Myeloperoxidase (MPO) is a highly potent oxidative enzyme that is capable of inducing both oxidative and nitrosative stress in vivo.
  
  
  
  To determine if and the extent to which MPO-generated oxidants contribute to brain I/R injury, we treated mice subjected to middle cerebral artery occlusion (MCAO) with N-acetyl lysyltyrosylcysteine amide (KYC), a novel, specific and non-toxic inhibitor of MPO. Behavioral testing, ischemic damage, blood-brain-barrier disruption, apoptosis, neutrophils infiltration, microglia/macrophage activation, and MPO oxidation were analyzed within a 7-day period after MCAO.
  
  
  
  Our studies show that KYC treatment significantly reduces neurological severity scores, infarct size, IgG extravasation, neutrophil infiltration, loss of neurons, apoptosis, and microglia/macrophage activation in the brains of MCAO mice. Immunofluorescence studies show that KYC treatment reduces the formation of chlorotyrosine (ClTyr), a fingerprint biomarker of MPO oxidation, nitrotyrosine (NO2Tyr), and 4-hydroxynonenal (4HNE) in MCAO mice. All oxidative products colocalized with MPO in the infarcted brains, suggesting that MPO-generated oxidants are involved in forming the oxidative products.
  
  
  
  MPO-generated oxidants play detrimental roles in causing brain damage after stroke which is effectively reduced by KYC.
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Yu
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA.|Department of Breast Surgery, Maternal and Child Health Hospital of Hubei Province, 745 WuLuo Road, Hongshan District, Wuhan City, Hubei Province, 430070, China.
authors.forename: Ziming
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA.
authors.forename: Deron W
authors.initials: DW
authors.lastname: Jones
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA.
authors.forename: Kirkwood A
authors.initials: KA
authors.lastname: Pritchard
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI, 53226, USA. hzhang@mcw.edu.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D001930:Brain Injuries / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; C588227:N-acetyllysyltyrosylcysteine amide; D018696:Neuroprotective Agents; D009842:Oligopeptides; D016877:Oxidants; D016159:Tumor Suppressor Protein p53; D009195:Peroxidase; D052248:Nitric Oxide Synthase Type I
keywords: Middle cerebral artery occlusion (MCAO); Myeloperoxidase; N-acetyl lysyltyrosylcysteine amide (KYC); Oxidative stress; Stroke