Progress in Neuro-Psychopharmacology and Biological Psychiatry
Memantine decreases hippocampal glutamate levels: A magnetic resonance spectroscopy study
Introduction
Glutamate (Glu) excitotoxicity through N-methyl-d-aspartic acid receptor (NMDAr) is a feature of Alzheimer's disease (AD) (Lipton, 2004). Glutamate is the main excitatory neurotransmitter in hippocampal circuits (Ottersen, 1991) and the hippocampus, crucial for memory performance, is an early affected target in the course of AD. Memantine, an NMDAr antagonist, is an approved treatment of moderate to severe AD. The mechanism of memantine is based on the modulation of NMDAr stimulation by glutamate. Recent reports suggest that it is also effective in mild to moderate stages (Bakchine and Loft, 2007).
Proton magnetic resonance spectroscopy (1H-MRS) enables a non-invasive sampling of biochemical composition of the brain. Studies of hippocampal region show a reduction in N-acetylaspartate (NAA) levels (Schuff et al., 1997, Block et al., 2002) in AD patients as compared with normal controls. Some authors suggested that the decrease in NAA was a disease, but not age-related phenomenon, as they observed that NAA levels declined significantly with age in the frontal cortex, but not in the hippocampus (Chen et al., 2000). Also reduction in cortical glutamate was reported in a few single voxel 1H-MRS AD studies (Antuono et al., 2001, Hattori et al., 2002), but the effects of memantine on in vivo hippocampal glutamate levels have not been examined.
Section snippets
Subjects
The subjects were recruited at the Center for Brain Health of the New York University (NYU) School of Medicine. They gave their written informed consent to NYU IRB (Institutional Review Board) approved protocols and received clinical assessments (general medical, neurological, psychiatric, and laboratory examinations) and an MRI (to exclude possible confounding comorbidities affecting cognition). The assessment included a Mini Mental State Examination (MMSE) (Folstein, 1983) and a Global
1H-MRS
Sample spectra from a paraxial slice containing the bilateral hippocampi of a 72 year old healthy female elderly control are shown in Fig. 3, superimposed on the MRI from the corresponding slice for anatomical reference. Metabolic maps from this slice are also presented to demonstrate the quality of localization, as reflected by the metabolic voids in the cerebrospinal fluid (CSF) spaces.
The SNRs for the metabolites, defined as their peak-height divided by twice the root-mean-square of the
Discussion
This clinical data shows that treatment with an uncompetitive NMDAr antagonist (memantine) decreases the Glu/Cr in the hippocampus. Others have observed an increase in cingulate glutamatergic turnover (Rowland et al., 2005) and an increase in frontal and cingulate blood flow, a surrogate for glutamate release (Holcomb et al., 2005), after acute ketamine administration. Moreover, in animal hippocampal homogenates ketamine stimulated the phosphate-activated glutaminase (PAG) activity (an enzyme
Conclusion
Overall, the results suggest that memantine decreases hippocampal Glu/Cr, possibly consistent with this drug's anti-excitotoxic properties. As decline in neuronal function cannot be entirely rejected, these data require replication with larger samples sizes.
Acknowledgements
We thank Drs. Andrew A. Maudsley of the University of Miami and Brian J. Soher of Duke University for the use of the SITools-FITT spectral modeling software, Ms. Rachel Mistur and Schantel Williams for cognitive testing and Ms. Nissa Perry for coordination of the MR evaluations. This study was supported by Forest Laboratories, Inc., NIH grants: AG12101, AG 22374, AG0305, P30 AG08051, EB01015 and NS050520, and a grant from the Mentored Medical Student Clinical Research (MMSCR) Program NCRR
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