TY - JOUR
T1 - A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis
AU - Offen, Daniel
AU - Gilgun-Sherki, Yossi
AU - Barhum, Yael
AU - Benhar, Moran
AU - Grinberg, Leonid
AU - Reich, Reuven
AU - Melamed, Eldad
AU - Atlas, Daphne
PY - 2004/6
Y1 - 2004/6
N2 - 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 Cu2+, 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.
AB - 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 Cu2+, 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.
KW - AD4
KW - Blood-brain barrier
KW - Experimental autoimmune encephalomyelitis
KW - Multiple sclerosis
KW - Oxidative stress
KW - Reactive oxygen species
KW - Thiol-antioxidants
UR - http://www.scopus.com/inward/record.url?scp=2642579050&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2004.02428.x
DO - 10.1111/j.1471-4159.2004.02428.x
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 15147517
AN - SCOPUS:2642579050
SN - 0022-3042
VL - 89
SP - 1241
EP - 1251
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 5
ER -