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Blocking glutamate carboxypeptidase II inhibits glutamate excitotoxicity and regulates immune responses in experimental autoimmune encephalomyelitis
Author(s) -
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 IkHyun,
Jee Youngheun
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13816
Subject(s) - experimental autoimmune encephalomyelitis , glutamate carboxypeptidase ii , excitotoxicity , glutamate receptor , astrocyte , multiple sclerosis , encephalomyelitis , immunology , immune system , biology , central nervous system , neuroscience , chemistry , biochemistry , receptor , prostate , genetics , cancer
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 mG luR1 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 .