The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence
Article first published online: 27 AUG 2003
Copyright © 2003 John Wiley & Sons, Ltd.
International Journal of Geriatric Psychiatry
Supplement: Memantine Workshop 2001, Barcelona, Spain
Volume 18, Issue Supplement 1, pages S23–S32, September 2003
How to Cite
Danysz, W. and Parsons, C. G. (2003), The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence. Int. J. Geriat. Psychiatry, 18: S23–S32. doi: 10.1002/gps.938
- Issue published online: 27 AUG 2003
- Article first published online: 27 AUG 2003
- Manuscript Accepted: 25 NOV 2002
- NMDA receptors;
- Alzheimer's dementia;
- cognitive enhancement
There is increasing evidence for the involvement of glutamate-mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD). We suggest that glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner in this disorder. This continuous mild activation may lead to neuronal damage and impairment of synaptic plasticity (learning). It is likely that under such conditions Mg2+ ions, which block NMDA receptors under normal resting conditions, can no longer do so. We found that overactivation of NMDA receptors using a direct agonist or a decrease in Mg2+ concentration produced deficits in synaptic plasticity (in vivo: passive avoidance test and/or in vitro: LTP in the CA1 region). In both cases, memantine—an uncompetitive NMDA receptor antagonists with features of an ‘improved’ Mg2+ (voltage-dependency, kinetics, affinity)—attenuated this deficit. Synaptic plasticity was restored by therapeutically-relevant concentrations of memantine (1 μM). Moreover, doses leading to similar brain/serum levels provided neuroprotection in animal models relevant for neurodegeneration in AD such as neurotoxicity produced by inflammation in the NBM or β-amyloid injection to the hippocampus. As such, if overactivation of NMDA receptors is present in AD, memantine would be expected to improve both symptoms (cognition) and to slow down disease progression because it takes over the physiological function of magnesium. Copyright © 2003 John Wiley & Sons, Ltd.