AMPA receptor potentiators as cognitive enhancers

With an aging population, cognitive decline as a result of aging, Alzheimer's disease and other neurological conditions has become a major problem. Many of the current medications (eg, acetylcholinesterase inhibitors) for cognitive disorders show limited efficacy and are effective only in certain populations. Several other pharmacological pathways are therefore being explored in an attempt to develop superior medications. Glutamate and glutamate receptors are well recognized to play a key role in long-term potentiation (LTP), a process that is believed to underlie memory formation. Glutamate antagonists have been demonstrated to block LTP and to disrupt memory in both rodents and humans. Based on these data, it is not surprising that boosting glutamatergic transmission has been explored as a means of enhancing cognition. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors have been demonstrated to control fast synaptic transmission. Several classes of AMPA receptor potentiators have been described in the last decade. These molecules bind to allosteric sites on AMPA receptors, slow desensitization and thereby enhance signaling through the receptors. Some AMPA receptor potentiator agents have been explored in rodent models and are now entering clinical trials. Research complexity for these agents arises from the multiple AMPA receptor subtypes on which the molecules can act differentially, as well as from the distribution of AMPA receptors and the difficulty in studying cognition in naïve rodents. Nevertheless, boosting Ca(2+) flux through the AMPA receptor, and enhancing LTP and downstream pathways may provide a novel approach to the treatment of cognitive deficits.