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.

Fig. 1.

GCPII reaction. GCPII cleaves NAAG into NAA and glutamate.

Fig. 2.

Positive correlations of cognitive task performances to right hippocampal (NAAG/Cr). Performance on the written (A) and oral (B) Symbol Digit Modalities Test positively correlated to right hippocampal (NAAG/Cr) in MS patients. (A, P < 0.001, r = 0.9129; B, P < 0.001, r = 0.9163) Performance on the 2-s (C) and 3-s (D) Paced Auditory Serial Addition Test positively correlated to right hippocampal (NAAG/Cr) in patients with multiple sclerosis (C, P < 0.01, r = 0.8644; D, P < 0.05, r = 0.7774). No differences were noted in other metabolites examined (E). n = 9 patients.

Fig. 3.

Effect of 2-PMPA on disease score, cognition, and frontal cortex NAAG concentration in EAE mice. (A) Daily administration of 2-PMPA does not affect EAE severity compared with vehicle-treated mice. (B) EAE mice treated with 2-PMPA demonstrated improved Barnes maze performance as indicated by increased total latency delta (day 1 total latency − day 4 total latency) and decreased path efficiency delta (day 1 path efficiency − day 4 path efficiency) compared with controls, showing superior learning abilities. (C) Sample Barnes maze paths tracked by ANY-maze software of the first trial of day 1 or day 4 of Barnes maze testing (∼4 wk post-EAE induction). TL, total latency; PE, path efficiency. Underlined number is represented in the plot, and the number in parentheses represents the group average. (D) Daily administration of 2-PMPA increases cue-based freezing behavior, an indication of improved memory, in a fear conditioning test. (E) NAAG concentration in the frontal cortex is elevated in EAE-positive mice receiving daily injections of 2-PMPA. Significantly different at *P < 0.05, **P < 0.01, ***P < 0.001. n = 10 mice per group.