Premium
A low molecular weight copper chelator crosses the blood–brain barrier and attenuates experimental autoimmune encephalomyelitis
Author(s) -
Offen Daniel,
GilgunSherki Yossi,
Barhum Yael,
Benhar Moran,
Grinberg Leonid,
Reich Reuven,
Melamed Eldad,
Atlas Daphne
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02428.x
Subject(s) - experimental autoimmune encephalomyelitis , myelin oligodendrocyte glycoprotein , p38 mitogen activated protein kinases , blood–brain barrier , mapk/erk pathway , kinase , chemistry , multiple sclerosis , matrix metalloproteinase , encephalomyelitis , inflammation , microbiology and biotechnology , biochemistry , biology , immunology , endocrinology , central nervous system
Increasing evidence suggests that enhanced production of reactive oxygen species (ROS) activates the MAP kinases, c‐Jun N‐terminal protein kinase (JNK) and mitogen‐activated protein kinase MAPK (p38). These phosphorylated intermediates at the stress‐activated pathway induce expression of matrix metalloproteinases (MMPs), leading to inflammatory responses and pathological damages involved in the etiology of multiple sclerosis (MS). Here we report that N ‐acetylcysteine amide (AD4) crosses the blood–brain barrier (BBB), chelates Cu 2+ , which catalyzes free radical formation, and prevents ROS‐induced activation of JNK, p38 and MMP‐9. In the myelin oligodendrocyte glycoprotein (MOG)‐induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, oral administration of AD4 drastically reduced the clinical signs, inflammation, MMP‐9 activity, and protected axons from demylination damages. In agreement with the in vitro studies, we propose that ROS scavenging by AD4 in MOG‐treated animals prevented MMP's induction and subsequent damages through inhibition of MAPK pathway. The low toxicity of AD4 coupled with BBB penetration makes this compound an excellent potential candidate for the therapy of MS and other neurodegenerative disorders.