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- Title
Inhibition of myeloperoxidase oxidant production by N-acetyl lysyltyrosylcysteine amide reduces brain damage in a murine model of stroke.
- Authors
Guoliang Yu; Ye Liang; Ziming Huang; Jones, Deron W.; Pritchard Jr., Kirkwood A.; Hao Zhang; Yu, Guoliang; Liang, Ye; Huang, Ziming; Pritchard, Kirkwood A Jr; Zhang, Hao
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>MPO-generated oxidants play detrimental roles in causing brain damage after stroke which is effectively reduced by KYC.
- Subjects
MYELOPEROXIDASE; OXIDATIVE stress; STROKE; BRAIN damage; ANTERIOR cerebral artery; PROTEIN metabolism; ANIMAL experimentation; ANIMALS; APOPTOSIS; BIOLOGICAL models; BLOOD-brain barrier; BRAIN injuries; CALCIUM-binding proteins; CELLS; GENES; IMMUNITY; INFARCTION; MACROPHAGES; MICE; MICROFILAMENT proteins; MOTOR ability; OLIGOPEPTIDES; OXIDIZING agents; OXIDOREDUCTASES; RESEARCH funding; DISEASE complications; NEUROPROTECTIVE agents; PHARMACODYNAMICS; PHYSIOLOGY; THERAPEUTICS
- Publication
Journal of Neuroinflammation, 2016, Vol 13, p1
- ISSN
1742-2094
- Publication type
journal article
- DOI
10.1186/s12974-016-0583-x