title: Inhibition of glutamate carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis.
abstract: Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Brain Science Institute, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Rahn
authors.forename: Crystal C
authors.initials: CC
authors.lastname: Watkins
authors.forename: Jesse
authors.initials: J
authors.lastname: Alt
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.forename: Marigo
authors.initials: M
authors.lastname: Stathis
authors.forename: Inna
authors.initials: I
authors.lastname: Grishkan
authors.forename: Ciprian M
authors.initials: CM
authors.lastname: Crainiceau
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.forename: Jason
authors.initials: J
authors.lastname: Brandt
authors.forename: Peter B
authors.initials: PB
authors.lastname: Barker
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Adam I
authors.initials: AI
authors.lastname: Kaplin
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D060825:Cognitive Dysfunction / Q000201:enzymology* / Q000209:etiology; D004151:Dipeptides / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications*; D005260:Female; D005434:Flow Cytometry; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000150:complications*; D009483:Neuropsychological Tests; D009943:Organophosphorus Compounds
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D004151:Dipeptides; D009943:Organophosphorus Compounds; C027172:isospaglumic acid; D043425:Glutamate Carboxypeptidase II