A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis

Daniel Offen, Yossi Gilgun-Sherki, Yael Barhum, Moran Benhar, Leonid Grinberg, Reuven Reich, Eldad Melamed, Daphne Atlas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1241-1251
Number of pages11
JournalJournal of Neurochemistry
Volume89
Issue number5
DOIs
StatePublished - Jun 2004

Keywords

  • AD4
  • Blood-brain barrier
  • Experimental autoimmune encephalomyelitis
  • Multiple sclerosis
  • Oxidative stress
  • Reactive oxygen species
  • Thiol-antioxidants

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