AMPA Receptors as Pharmacotherapeutic Sites

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AMPA receptors are widespread in the brain, including most regions of the cerebral cortex, hippocampus, amygdala, thalamus, hypothalamus, brain stem, and spinal cord. The regional variations in expression of the subunits, splice variants, and editing efficiency are apparent and are probably involved in local and global network function. AMPA receptors are being studied as potential therapeutic targets in diseases such as Alzheimer's disease, cerebrovascular disease (preventive and poststroke), epilepsy, schizophrenia, neural trauma, and other conditions involving cognitive impairments. Such promise has been raised by the successes reported for AMPA agonists (AMPAmimetics or AMPAkines) to enhance maze learning in age-associated memory impairment in mice and for antagonists (blockers) to prevent the spread of necrosis in ischemic events. Agonists (such as CX516 and aniracetam) and antagonists of varying specificity for AMPA receptor variants are being studied, with goals of safer and more effective treatments for direct injury prevention due to toxins, ischemia, hypoxia, physical and emotional trauma, hypoglycemia, hy-percortisolemia, neurodegenerative mechanisms, neuro-developmental disorders, cognitive disorders, and epilepsy. A whole new array of selective clinical pharmacotherapeu-tics are based on allosteric modulators that are noncom-petitive AMPA receptor antagonists, such as the 2,3-benzodiazepines GYKI 52466, GYKI 53773, and LY404187 may be clinically useful for treatment of movement disorders (like spasticity and Parkinson's disease), epilepsy, ischemia, and a wide variety of neurodegenerative diseases. Cognition enhancers such as aniracetam and CX516 may be useful for improvement of the cognitive deficits of disorders ranging from Alzheimer's disease to Schizophrenia. Pharmaceutical chemistry is advancing to the level of GluR1-4 subunit and splice form specificity, which is bringing a large number of drugs closer to clinical trials for some of the most common and devastating brain pathologies. Future work will hopefully also begin to elucidate the regulatory mechanisms behind GluR1-4 subunit and splice form assembly, homeostasis, regional specificity, and region-to-region signaling, of which very little is currently known.

REFERENCES

Dingledine, R., Borges, K., Bowie, D., & Traynelis, S. F. (1999). The glutamate receptor ion channels. Pharmacological Reviews, 51(1), 7-61.

Luscher, C., Nicoll, R. A., Malenka, R. C., & Muller, D. (2000). Synaptic plasticity and dynamic modulation of the postsynap-tic membrane. Nature Neuroscience, 3, 545-550.

J. Thomas Noga

Emory University

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