The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence
Abstract
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 Mg(2+) 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 Mg(2+) 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' Mg(2+) (voltage-dependency, kinetics, affinity)-attenuated this deficit. Synaptic plasticity was restored by therapeutically-relevant concentrations of memantine (1 microM). 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 beta-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.
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Memantine has been used clinically to treat AD patients, and its beneficial effects may be explained by partial antagonism of NMDAR activity.
“Notably, a NMDA antagonist, memantine, has been used clinically to treat AD patients. The beneficial effects of memantine may be explained partial antagonism of NMDAR activity [70].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [70]
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- Authors
- Danysz, W., & Parsons, C. G.
- Affiliations
- Merz (Germany) (DE)
- Corresponding author
- Danysz, Wojciech
- Venue
- International Journal of Geriatric Psychiatry
- Publisher
- Wiley
- Published
- 2003
- Volume
- 18
- Issue
- S1
- Pages
- S23-S32
- ISSN
- 0885-6230 (ISSN-L)
- 1099-1166
- OpenAlex
- W2117396078
- Cited by
- 404
- References
- 49
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 20 · 2023: 20 · 2022: 18 · 2021: 18 · 2020: 19 · 2019: 16 · 2018: 11 · 2017: 10 · 2016: 14 · 2015: 17 · 2014: 21 · 2013: 17 · 2012: 16
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Geriatric Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- memantine, Alzheimer's disease, NMDA receptor antagonism, glutamate excitotoxicity, magnesium, synaptic plasticity, long-term potentiation, hippocampal CA1, neuroprotection, amyloid-beta, neuroinflammation, cognitive impairment
- MeSH terms
- Aged, Alzheimer Disease, Drug Evaluation, Preclinical, Humans, Memantine, Neuronal Plasticity, Receptors, N-Methyl-D-Aspartate, Excitatory Amino Acid Antagonists, Neuroprotective Agents
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