title: A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis.
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 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.
authors.affiliation: Neurology Department and Felsenstein Medical Research Center Tel Aviv University, Rabin Medical Center, Petah-Tikva, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
authors.forename: Yossi
authors.initials: Y
authors.lastname: Gilgun-Sherki
authors.forename: Yael
authors.initials: Y
authors.lastname: Barhum
authors.forename: Moran
authors.initials: M
authors.lastname: Benhar
authors.forename: Leonid
authors.initials: L
authors.lastname: Grinberg
authors.forename: Reuven
authors.initials: R
authors.lastname: Reich
authors.forename: Eldad
authors.initials: E
authors.lastname: Melamed
authors.forename: Daphne
authors.initials: D
authors.lastname: Atlas
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability; D002614:Chelating Agents / Q000378:metabolism* / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008970:Molecular Weight; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000964:Antimetabolites, Antineoplastic; D002614:Chelating Agents; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; C487056:N-Acetylcysteinamide; D003300:Copper; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D000111:Acetylcysteine