Monday, 26 November 2012

Research: Glutamate Carboxypeptidase II and Cognition.

Epub: Rahn et al. Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis. Proc Natl Acad Sci U S A. 2012 Nov . 

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.

The conclusions say it all, The picture above is not a table but a Barnes Maze where an animal learns where the hidden box is located. The drug was given to mice with MS like disease and they were better at learning where the hidden box was. This was given all the time during the experiment and showed not be that it improved learning but that it stopped the loss of learning ability. It would have been better if they had let the animals acquire a deficit and then seen if there was improvement as this is more applicable to how it would be used in MSers. Interestingly it has been suggestive that this class of drug, i.e. GCPII inhibitor can inhibit excitotoxic glutamate and thus have the potential to induce neuroprotection, which was not seen in the EAE mice, but has been seen in other neurodegenerative models, possibly via activity on metabotrophic glutamate receptors. Symptomatic trials are much shorter than trials for progressive disease, so a symptomatic agent which has other beneficial effects was some advantage as it should be quicker to get to MSers. However this logic failed with cannabinoids as people do not seem to have good access to them


  1. Are GCPII inhibitors available and used for other things?

  2. They have been tested in other conditions but I am not aware of a commercially available drug licenced for human use. You may now different..


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