title: Blocking glutamate carboxypeptidase II inhibits glutamate excitotoxicity and regulates immune responses in experimental autoimmune encephalomyelitis.
abstract: Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in the murine central nervous system (CNS) and recapitulates the clinical and pathological features of human multiple sclerosis (MS). Glutamate carboxipeptidase II (GCPII), an enzyme expressed exclusively on astrocytes, is known to affect the disease progression of various neurological disorders by producing glutamate. Despite several findings indicating possible link between glutamate and MS/EAE, however, the involvement of astrocyte or GCPII on glutamate excitotoxicity has not received much attention in MS/EAE. When we examined GCPII expression during EAE progression in this study, we observed significantly elevated GCPII expression in peak stage of disease localized mainly in astrocytes. Intrigued by these results, we tried a potent GCPII inhibitor, 2-phosphonomethyl pentanedioic acid (2-PMPA), on EAE mice and noticed markedly attenuated EAE clinical signs along with significantly inhibited infiltration of inflammatory cells into CNS. Furthermore, 2-PMPA dampened the function of Th1 cell lineage and down-regulated mGluR1 expression in both periphery and CNS contributing to glutamate-mediated immune regulation. Our observations identify a sequence of events triggering EAE through GCPII overexpression, which may offer a novel therapeutic approach to the treatment of MS.
authors.affiliation: College of Veterinary Medicine, Jeju National University, South Korea.
authors.forename: Danbee
authors.initials: D
authors.lastname: Ha
authors.affiliation: College of Veterinary Medicine, Jeju National University, South Korea.
authors.forename: So Jin
authors.initials: SJ
authors.lastname: Bing
authors.affiliation: Department of Marine Bio-Food Sciences, Chonnam National University, Yeosu, South Korea.
authors.forename: Ginnae
authors.initials: G
authors.lastname: Ahn
authors.affiliation: College of Veterinary Medicine, Jeju National University, South Korea.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Jeju National University, South Korea.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Cho
authors.affiliation: Department of Advanced Convergence Technology & Science, Jeju National University, South Korea.
authors.forename: Areum
authors.initials: A
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Jeju National University, South Korea.
authors.forename: Kalahe H I N M
authors.initials: KH
authors.lastname: Herath
authors.affiliation: Department of Parasitology, School of Medicine, Pusan National University, Yangsan, South Korea.
authors.forename: Hak Sun
authors.initials: HS
authors.lastname: Yu
authors.affiliation: Department of Nanobiomedical Science & BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, South Korea.|Department of Pharmacology, College of Pharmacy, Dankook University, Cheonan, South Korea.
authors.forename: Sangmee Ahn
authors.initials: SA
authors.lastname: Jo
authors.affiliation: Department of Convergence Medical Science, Brain Korea 21 Plus Program, and Institute of Korean Medicine, College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Ik-Hyun
authors.initials: IH
authors.lastname: Cho
authors.affiliation: College of Veterinary Medicine, Jeju National University, South Korea. yhjee@jejunu.ac.kr.|Department of Advanced Convergence Technology & Science, Jeju National University, South Korea. yhjee@jejunu.ac.kr.|Veterinary Medical Research Institute, Jeju National University, South Korea. yhjee@jejunu.ac.kr.
authors.forename: Youngheun
authors.initials: Y
authors.lastname: Jee
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011917:Rats, Inbred Lew; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014966:Xanthenes / Q000494:pharmacology
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D009943:Organophosphorus Compounds; D011480:Protease Inhibitors; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C102718:metabotropic glutamate receptor 3; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D043425:Glutamate Carboxypeptidase II
keywords: 2-phosphonomethyl pentanedioic acid; experimental autoimmune encephalomyelitis (EAE); glutamate carboxypeptidase II; glutamate excitotoxicity; metabotropic glutamate receptors