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Inhibition of myeloperoxidase oxidant production by N-acetyl lysyltyrosylcysteine amide reduces brain damage in a murine model of stroke. J Neuroinflammation 2016 05 24;13(1):119

Date

05/26/2016

Pubmed ID

27220420

Pubmed Central ID

PMC4879722

DOI

10.1186/s12974-016-0583-x

Scopus ID

2-s2.0-84973401203   27 Citations

Abstract

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: MPO-generated oxidants play detrimental roles in causing brain damage after stroke which is effectively reduced by KYC.

Author List

Yu G, Liang Y, Huang Z, Jones DW, Pritchard KA Jr, Zhang H

Author

Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Blood-Brain Barrier
Brain Infarction
Brain Injuries
Calcium-Binding Proteins
Disease Models, Animal
Gene Expression Regulation
Infarction, Middle Cerebral Artery
Macrophages
Mice
Mice, Inbred C57BL
Microfilament Proteins
Microglia
Motor Activity
Neuroprotective Agents
Neutrophil Infiltration
Nitric Oxide Synthase Type I
Oligopeptides
Oxidants
Peroxidase
Tumor Suppressor Protein p53
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a