Inhibition of glutamate carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis.
Proc Natl Acad Sci U S A
; 109(49): 20101-6, 2012 Dec 04.
Article
em En
| MEDLINE
| ID: mdl-23169655
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Glutamato Carboxipeptidase II
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Encefalomielite Autoimune Experimental
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Disfunção Cognitiva
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Hipocampo
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Esclerose Múltipla
Tipo de estudo:
Etiology_studies
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Prognostic_studies
Limite:
Adult
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Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos