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 300mg/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.