Medical College of Wisconsin
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Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood-brain barrier integrity and ameliorates disease severity. J Neurochem 2016 Feb;136(4):826-836

Date

11/13/2015

Pubmed ID

26560636

Pubmed Central ID

PMC4865458

DOI

10.1111/jnc.13426

Scopus ID

2-s2.0-84956732343

Abstract

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 5 days 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. We propose that during experimental autoimmune encephalomyelitis (EAE) onset macrophages and neutrophils migrate into the CNS and upon activation release myeloperoxidase (MPO) that promotes disruption of the blood-brain barrier (BBB) and disease progression. KYC restores BBB function by inhibiting MPO activity and in so doing ameliorates disease progression.

Author List

Zhang H, Ray A, Miller NM, Hartwig D, Pritchard KA, Dittel BN

Author

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




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