Journal
JOURNAL OF NEUROINFLAMMATION
Volume 13, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12974-016-0583-x
Keywords
Stroke; Myeloperoxidase; Oxidative stress; N-acetyl lysyltyrosylcysteine amide (KYC); Middle cerebral artery occlusion (MCAO)
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Funding
- Children's Research Institute of Children's Hospital of Wisconsin
- Medical College of Wisconsin
- National Heart, lung and blood institute [HL102836, HL112270]
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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 (NO(2)Tyr), 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.
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