Journal
JOURNAL OF NEUROCHEMISTRY
Volume 136, Issue 4, Pages 826-836Publisher
WILEY
DOI: 10.1111/jnc.13426
Keywords
blood-brain barrier; EAE; multiple sclerosis; myeloperoxidase
Categories
Funding
- NIH [R01 AI069358, R56 AI106672, R01 HL102836, R01 HL112270]
- BloodCenter Research Foundation
- National MS Society [RG 4975A1/2]
- American Heart Association [11SDG5120015]
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Oxidative stress is thought to contribute to disease pathogenesis in the central nervous system (CNS) disease multiple sclerosis (MS). Myeloperoxidase (MPO), a potent peroxidase that generates toxic radicals and oxidants, is increased in the CNS during MS. However, the exact mechanism whereby MPO drives MS pathology is not known. We addressed this question by inhibiting MPO in mice with experimental autoimmune encephalomyelitis (EAE) using our non-toxic MPO inhibitor N-acetyl lysyltyrosylcysteine amide (KYC). We found that therapeutic administration of KYC for 5days starting at the peak of disease significantly attenuated EAE disease severity, reduced myeloid cell numbers and permeability of the blood-brain barrier. These data indicate that inhibition of MPO by KYC restores blood-brain barrier integrity thereby limiting migration of myeloid cells into the CNS that drive EAE pathogenesis. In addition, these observations indicate that KYC may be an effective therapeutic agent for the treatment of MS.
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