Abstract
Memantine, an uncompetitive NMDA receptor antagonist used for the treatment of Alzheimer's disease (AD), has been hypothesized to have neuroprotective properties. However, the similarity of its mechanism of action to other NMDA receptor antagonists has led to concerns that it may also have neurotoxic effects. To assess both the neuroprotective and neurotoxic potential of memantine in a mouse model of AD (Tg2576 mice), we used quantitative light and electron microscopy to investigate the effects of long-term (6 months) administration of memantine (5, 10 and 20 mg/kg) on plaque deposition and neuronal morphology in the hippocampus and overlying cortex. A fear-conditioning paradigm was used to evaluate the behavioral consequences of any observed changes in structure. Administration of the two higher doses of memantine (10 and 20 mg/kg) was associated with a significant decrease in β-amyloid (Aβ) plaque deposition, increases in synaptic density and the appearance of degenerating axons; the latter two effects were independent of genotype. Administration of the lowest dose of memantine (5 mg/kg) was associated with a significant decrease in Aβ plaque deposition and a significant increase in synaptic density, but not a significant increase in degenerating axons. However, memantine did not significantly improve behavioral deficits associated with genotype in a fear-conditioning paradigm at any dose. These results suggest that chronic memantine administration may have both neuroprotective and neurotoxic effects in a mouse model of AD.
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Acknowledgements
This work was supported by MH060883 (JGC), AG 025824 (JGC), and 5P50AG0561 (HD).
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Dr Csernansky has received research grants from the NIMH, NIA, and royalties from Medtronic for a patent held jointly with Washington University School of Medicine, has been a paid consultant for Eli Lilly and Sanofi-Aventis, and has received speakers’ honoraria from Janssen Pharmaceutica, Eli Lilly and Bristol-Myers Squibb. The other authors report no conflicts of interest.
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Dong, H., Yuede, C., Coughlan, C. et al. Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease. Neuropsychopharmacol 33, 3226–3236 (2008). https://doi.org/10.1038/npp.2008.53
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DOI: https://doi.org/10.1038/npp.2008.53
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