title: Dose-dependent inhibition of GCPII to prevent and treat cognitive impairment in the EAE model of multiple sclerosis.
abstract: There are no treatments for cognitive impairment in multiple sclerosis (MS). Novel treatments can be evaluated in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS that displays both physical and cognitive impairments. Inhibition of the neuropeptidase glutamate carboxypeptidase II (GCPII) has previously been shown to ameliorate cognitive impairment in EAE, but dosing has not yet been optimized and only a prevention treatment paradigm has been explored. In the study described herein, the dose response of the GCPII inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) was evaluated for preventing cognitive impairment in EAE mice. Mice were immunized and received daily injections of vehicle or 2-PMPA (10, 30, 100, or 300 mg/kg) from the time of immunization (i.e. day 0). Although no doses of the drug altered physical disease severity, the 100mg/kg dose was most efficacious at preventing cognitive impairments in Barnes maze performance. Dose-related increases in brain NAAG levels were observed in post-mortem analysis, confirming target engagement. Using the 100mg/kg dose, we subsequently evaluated 2-PMPA׳s ability to treat EAE-induced symptoms by commencing treatment after the onset of physical signs of EAE (i.e. day 14). Mice were immunized for EAE and received daily injections of vehicle or 100mg/kg 2-PMPA starting two weeks post-immunization. Significant improvements in both cognitive performance and increases in brain NAAG levels were observed. GCPII inhibition is a promising treatment for cognitive impairment in MS, and doses providing equivalent exposures to 100mg/kg 2-PMPA in mice should be evaluated in clinical studies for the prevention and/or treatment of MS-related cognitive impairment.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Kristen R
authors.initials: KR
authors.lastname: Hollinger
authors.affiliation: Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Alt
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Riehm
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA. Electronic address: akaplin@jhmi.edu.
authors.forename: Adam I
authors.initials: AI
authors.lastname: Kaplin
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D003072:Cognition Disorders / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D004151:Dipeptides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications*; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000150:complications*; D009943:Organophosphorus Compounds / Q000008:administration & dosage*; D012720:Severity of Illness Index
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D004151:Dipeptides; D009943:Organophosphorus Compounds; C027172:isospaglumic acid; D001224:Aspartic Acid; C000179:N-acetylaspartate; D043425:Glutamate Carboxypeptidase II; C485064:Glutamate carboxypeptidase III, mouse
keywords: Cognition; GCPII; Glutamate; Mice; Multiple sclerosis; NAAG