The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
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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“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]
Citations
Cites
Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders
Epstein, F. H., Lipton, S. A., & Rosenberg, P. A. (1994) · New England Journal of Medicine · doi:10.1056/nejm199403033300907 · Cited by 2,676
Memantine in Moderate-to-Severe Alzheimer's Disease
Reisberg, B., Doody, R., Stöffler, A., Schmitt, F., Ferris, S., & Möbius, H. J. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa013128 · Cited by 2,043
Mattson, M. P., Cheng, B., Davis, D. G., Bryant, K., Lieberburg, I. M., & Rydel, R. E. (1992) · Journal of Neuroscience · doi:10.1523/jneurosci.12-02-00376.1992 · Cited by 1,633
The Time Course of Glutamate in the Synaptic Cleft
Clements, J. D., Lester, R. A. J., Tong, G., Jahr, C. E., & Westbrook, G. L. (1992) · Science · doi:10.1126/science.1359647 · Cited by 1,089
Pearson, R. C., Esiri, M. M., Hiorns, R. W., Wilcock, G. K., & Powell, T. P. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.13.4531 · Cited by 987
Parsons, C. G., Danysz, W., & Quack, G. (1999) · Neuropharmacology · doi:10.1016/s0028-3908(99)00019-2 · Cited by 900
Self-citationStaging of Alzheimer-Related Cortical Destruction
Braak, H., Braak, E., & Bohl, J. (2008) · European Neurology · doi:10.1159/000116984 · Cited by 836 · cited 2×
“Some authors have observed co-localisation of glutamatergic neurones and neurofibrillary tangles or senile plaques in the brains of AD patients (Pearson et al., 1985; Rogers and Morrison, 1985; Braak et al., 1993; Francis et al., 1993).”
Moechars, D., Dewachter, I., Lorent, K., Reversé, D., Baekelandt, V., Naidu, A., Tesseur, I., Spittaels, K., Haute, C. V. D., Checler, F., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.10.6483 · Cited by 668
β-Amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage
Koh, J., Yang, L. L., & Cotman, C. W. (1990) · Brain Research · doi:10.1016/0006-8993(90)91355-k · Cited by 617
Alternative excitotoxic hypotheses
Albin, R. L., & Greenamyre, J. T. (1992) · Neurology · doi:10.1212/wnl.42.4.733 · Cited by 574 · cited 1×
“An important aspect of this concept is the fact that an increase in glutamate levels per se is not necessarily required, because changes in receptors sensitivity and their overactivation by resting levels of glutamate could also contribute to neuronal death (Albin and Greenamyre, 1992).”
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Dong, X.-X., Wang, Y., & Qin, Z.-H. (2009) · Acta Pharmacologica Sinica · doi:10.1038/aps.2009.24 · Cited by 1,297
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994
Role of Glutamate and NMDA Receptors in Alzheimer’s Disease
Wang, R., & Reddy, P. H. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-160763 · Cited by 1,009
Parsons, C. G., Stöffler, A., & Danysz, W. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.07.013 · Cited by 724
Self-citationThe Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives
Wanka, L., Iqbal, K., & Schreiner, P. R. (2013) · Chemical Reviews · doi:10.1021/cr100264t · Cited by 712
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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