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Review
. 2024 Mar 27;25(7):3733.
doi: 10.3390/ijms25073733.

Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases

Allison Carles  1 , Aline Freyssin  1   2 , Florent Perin-Dureau  2 , Gilles Rubinstenn  2 , Tangui Maurice  1
Affiliations
Review

Targeting N-Methyl-d-Aspartate Receptors in Neurodegenerative Diseases

Allison Carles et al. Int J Mol Sci. .

Abstract

N-methyl-d-aspartate receptors (NMDARs) are the main class of ionotropic receptors for the excitatory neurotransmitter glutamate. They play a crucial role in the permeability of Ca2+ ions and excitatory neurotransmission in the brain. Being heteromeric receptors, they are composed of several subunits, including two obligatory GluN1 subunits (eight splice variants) and regulatory GluN2 (GluN2A~D) or GluN3 (GluN3A~B) subunits. Widely distributed in the brain, they regulate other neurotransmission systems and are therefore involved in essential functions such as synaptic transmission, learning and memory, plasticity, and excitotoxicity. The present review will detail the structure, composition, and localization of NMDARs, their role and regulation at the glutamatergic synapse, and their impact on cognitive processes and in neurodegenerative diseases (Alzheimer's, Huntington's, and Parkinson's disease). The pharmacology of different NMDAR antagonists and their therapeutic potentialities will be presented. In particular, a focus will be given on fluoroethylnormemantine (FENM), an investigational drug with very promising development as a neuroprotective agent in Alzheimer's disease, in complement to its reported efficacy as a tomography radiotracer for NMDARs and an anxiolytic drug in post-traumatic stress disorder.

Keywords: Alzheimer’s disease; N-methyl-d-aspartate receptor; fluoroethylnormemantine (FENM); neurodegenerative diseases.

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Conflict of interest statement

A.C. received a PhD grant from ReST Therapeutics; A.F. is an employee and co-inventor of patents from ReST Therapeutics; F.P.-D. is a co-founder and employee of ReST Therapeutics; G.R. is the founder and co-inventor of patents from ReST Therapeutics. T.M. is a co-inventor of patents from ReST Therapeutics.

Figures

Figure 2
Figure 2
The tripartite synapse comprising pre- and post-synaptic glutamatergic neurons, astrocytes, and microglia in (A) a healthy brain and (B) an AD patient brain. Glutamatergic excitotoxicity is induced by the accumulation of amyloid-ß aggregates in the synaptic cleft, interacting with post-synaptic NMDARs and astrocytic EAATs, leading to synaptic loss and impaired physiological and behavioral responses. Adapted from [26,43,62].
Figure 1
Figure 1
N-methyl-d-aspartate receptor (NMDAR) and its ligand binding sites. (A) NMDAR at resting potential is blocked by Mg2+. (B) NMDAR is activated by AMPAR-induced depolarization and binding of both Glu and Gly/D-Ser. Activation results in opening of channel and allows for voltage-dependent release of Mg2+ out of ionophore and Ca2+ influx into cell, inducing activation of PSD-95, signaling kinases, and mediating synaptic plasticity. (C) NMDAR uncompetitive antagonist binds PCP site and partially blocks influx of Ca2+ thus preventing neuronal membrane depolarization and downstream signaling mechanisms. Adapted from [15,26,27,33].
Figure 3
Figure 3
Structures of memantine and fluoroethylnormemantine. The PET radiotracer carries a 18F positron-emitting isotope [191,192].
See this image and copyright information in PMC

References

    1. Greenamyre J.T., Maragos W.F., Albin R.L., Penney J.B., Young A.B. Glutamate transmission and toxicity in Alzheimer’s disease. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 1988;12:421–430. doi: 10.1016/0278-5846(88)90102-9. - DOI - PubMed
    1. Reis H.J., Guatimosim C., Paquet M., Santos M., Ribeiro F.M., Kummer A., Schenatto G., Salgado J.V., Vieira L.B., Teixeira A.L., et al. Neuro-transmitters in the central nervous system & their implication in learning and memory processes. Curr. Med. Chem. 2009;16:796–840. doi: 10.2174/092986709787549271. - DOI - PubMed
    1. Dingledine R., Borges K., Bowie D., Traynelis S.F. The glutamate receptor ion channels. Pharmacol. Rev. 1999;51:7–61. - PubMed
    1. Volianskis A., France G., Jensen M.S., Bortolotto Z.A., Jane D.E., Collingridge G.L. Long-term potentiation and the role of N-methyl-d-aspartate receptors. Brain Res. 2015;1621:5–16. doi: 10.1016/j.brainres.2015.01.016. - DOI - PMC - PubMed
    1. Lynch G., Baudry M. The biochemistry of memory: A new and specific hypothesis. Science. 1984;8:1057–1063. doi: 10.1126/science.6144182. - DOI - PubMed

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