P.K.-Y.C. and D.V. contributed equally to this work.
AMPA receptors as drug targets in neurological disease – advantages, caveats, and future outlook
Article first published online: 19 JUN 2012
© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Special Issue: EARLY BRAIN REPAIR AND PROTECTION
Volume 35, Issue 12, pages 1908–1916, June 2012
How to Cite
Chang, P. K.-Y., Verbich, D. and McKinney, R. A. (2012), AMPA receptors as drug targets in neurological disease – advantages, caveats, and future outlook. European Journal of Neuroscience, 35: 1908–1916. doi: 10.1111/j.1460-9568.2012.08165.x
- Issue published online: 19 JUN 2012
- Article first published online: 19 JUN 2012
- Received 22 February 2012, revised 13 April 2012, accepted 15 April 2012
- Alzheimer’s disease;
- dendritic spines;
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.