Cited by 155Neuroscience and Neuropharmacology ResearchAmino Acid Enzymes and MetabolismAlzheimer's disease research and treatments

AMPA receptors as drug targets in neurological disease—advantages, caveats, and future outlook

Chang, Philip K.‐Y., Verbich, David, McKinney, R. Anne·2012·European Journal of Neuroscience

Abstract

Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor function are altered, thus making AMPA receptors potential therapeutic targets for clinical intervention. The work summarized in this review suggests a link between AMPA receptor function and debilitating neuropathologies, and discusses the current state of therapies targeting AMPA receptors in four diseases. In amyotrophic lateral sclerosis, AMPA receptors allow cytotoxic levels of calcium into neurons, leading to motor neuron death. Likewise, in some epilepsies, overactivation of AMPA receptors leads to neuron damage. The same is true for ischemia, where oxygen deprivation leads to excitotoxicity. Conversely, Alzheimer's disease is characterized by decreased AMPA activation and synapse loss. Unfortunately, many clinical studies have had limited success by directly targeting AMPA receptors in these diseases. We also discuss how the use of AMPA receptor modulators, commonly known as ampakines, in neurological diseases initially seemed promising in animal studies, but mostly ineffective in clinical trials. We propose that indirectly affecting AMPA receptors, such as by modulating transmembrane AMPA receptor regulatory proteins or, more generally, by regulating glutamatergic transmission, may provide new therapeutic potential for neurological disorders.

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Crossref · 10.1111/j.1460-9568.2012.08165.x

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Authors
Chang, P. K. ‐., Verbich, D., & McKinney, R. A.
Affiliations
McGill University (CA)
Corresponding author
McKinney, R. Anne
Venue
European Journal of Neuroscience
Publisher
Wiley
Published
2012-06
Volume
35
Issue
12
Pages
1908-1916
ISSN
  • 0953-816X (ISSN-L)
  • 1460-9568
OpenAlex
W1935337388
Cited by
155
References
144
Citations by year
2026: 4 · 2025: 8 · 2024: 9 · 2023: 14 · 2022: 10 · 2021: 8 · 2020: 10 · 2019: 17 · 2018: 12 · 2017: 8 · 2016: 12 · 2015: 16 · 2014: 6 · 2013: 19 · 2012: 2
FWCI
1.46
Type
journal article
Language
en
Open access
closed
Locations
  • European Journal of Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • McGill University
  • Canadian Institutes of Health Research (86724_1)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
AMPA receptors, ionotropic glutamate receptors, therapeutic target, neurological disorders, amyotrophic lateral sclerosis, epilepsy, excitotoxicity, ischemia, Alzheimer's disease, synaptic loss, ampakines, transmembrane AMPA receptor regulatory proteins, glutamatergic neurotransmission, motor neuron degeneration
MeSH terms
Alzheimer Disease, Amyotrophic Lateral Sclerosis, Animals, Epilepsy, Humans, Nervous System Diseases, Receptors, AMPA, Neurotransmitter Agents, Excitatory Postsynaptic Potentials, Mice, Rats, Molecular Targeted Therapy

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