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

Eur J Neurosci. 2012 Jun;35(12):1908-16. doi: 10.1111/j.1460-9568.2012.08165.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / physiopathology
  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Epilepsy / drug therapy
  • Epilepsy / physiopathology
  • Excitatory Postsynaptic Potentials / drug effects
  • Humans
  • Mice
  • Molecular Targeted Therapy / trends
  • Nervous System Diseases / drug therapy*
  • Neurotransmitter Agents / pharmacology
  • Neurotransmitter Agents / therapeutic use
  • Rats
  • Receptors, AMPA / agonists
  • Receptors, AMPA / antagonists & inhibitors*
  • Receptors, AMPA / physiology

Substances

  • Neurotransmitter Agents
  • Receptors, AMPA