AMPA receptors as drug targets in neurological disease—advantages, caveats, and future outlook
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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Dopamine depletion in the striatum leads to loss of dendritic spines on striatal medium spiny neurons in animal models and in Parkinson's disease.
“DA-depletion in the striatum leads to the loss of dendritic spines on striatal medium spiny neurons (MSNs) in both animal models87–89 and in PD90.”
From Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease (2013) · cites this paper as [90]
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Role of Ion Channels in Alzheimer’s Disease Pathophysiology
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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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