Investigating the Inhibitory Effect of Fatty Acids on NMDA Receptor

Previous research has showed that AMPA receptor can be used as a molecular target for anti-epileptic drugs, and there is evidence of an inhibitory effect of several fatty acids on AMPA receptor, for example, D ecanoic A cid (DA), 4- E thyl O ctanoic A cid (4EOA) and 4- B utyl c y C loheaxne C arboxylic A cid (4BCCA). However, as NMDA receptor and AMPA receptor are quite similar in structures and are widely distributed in CNS, there is a concern on whether the three fatty acids also have an effect on NMDA receptor, and NMDA receptor inhibition may result in some unwanted side effects, such as hallucinations, nightmares, and memory loss. Two-electrode voltage clamp was performed on the oocytes of Xenopus Laevis expressing the NMDAR subunit GluN1/N2A, to record agonist evoked inward currents generated from oocytes exposed to different concentrations of fatty acid solutions. On further examination it was found that all of the three acids have some inhibitory effect on NMDA recceptor, and seem to act as non-competitive antagonists. The 4EOA has the strongest inhibition effect on NMDA receptor, followed by 4BCCA and DA. However, the three fatty acids only have a clear inhibitory effect when the concentration of the corresponding fatty acid is higher than 500 µM, which is considered high for clinical use. Moreover, the fatty acids tested had a stronger inhibitory effect on NMDA receptor containing the GluN1/N2B subunits.