Blocking glutamate carboxypeptidase II inhibits glutamate excitotoxicity and regulates immune responses in experimental autoimmune encephalomyelitis. (11th August 2016)

• Record Type: Journal Article
• Authors: Ha, Danbee; Bing, So Jin; Ahn, Ginnae; Kim, Jinhee; Cho, Jinhee; Kim, Areum; Herath, Kalahe H. I. N. M.; Yu, Hak Sun; Jo, Sangmee Ahn; Cho, Ik‐Hyun; Jee, Youngheun
• Is Part Of: FEBS journal. Volume 283:Number 18(2016)
• Page Start: 3438
• Page End: 3456
• Publication Date: 2016-08-11
• Subjects: 2‐phosphonomethyl pentanedioic acid -- experimental autoimmune encephalomyelitis (EAE) -- glutamate carboxypeptidase II -- glutamate excitotoxicity -- metabotropic glutamate receptors; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.13816
• Languages: English
• ISSNs: 1742-464X

Abstract

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. Abstract : Proposed role of GCPII inhibitor (2‐PMPA) on EAE progression. 2‐PMPA treatment not only reduces glutamate‐induced Th1/Th17 T‐cell response by suppressing mGluR1 expression but also activates mGluR3 signals which reduce glutamate release by inhibiting NAAG degradation. Reduced glutamate production by GCPII inhibition consequently ameliorates EAE severity and detrimental axonal damages by inhibiting excessive T‐cell response and gliosis.