Modulation of Glutamate and Glycine Transporters by Niflumic, Flufenamic and Mefenamic Acids

Abstract

Three fenamates--niflumic, flufenamic and mefenamic acids--were tested for effects on substrate-induced currents of glutamate and glycine transporters (EAAT1, EAAT2, GLYT1b and GLYT2a) expressed in Xenopus laevis oocytes. All fenamates inhibited EAAT1 currents; 100 microM flufenamic acid produced the most inhibition, decreasing the I (max) by 53 +/- 4% (P < 0.001). EAAT2 currents were less sensitive, but 100 microM flufenamic acid inhibited the I (max) by 34 +/- 5% (P = 0.006). All fenamates inhibited GLYT1b currents; 100 microM flufenamic acid produced the most inhibition, decreasing the I (max) by 61 +/- 1% (P < 0.001). At 100 microM, effects on the GLYT2a I (max) were mixed: 13 +/- 2% inhibition by flufenamic acid (P = 0.002), 30 +/- 6% enhancement by niflumic acid (P = 0.002), and no effect by mefenamic acid. Minor effects on substrate affinity suggested non-competitive mechanisms. These data could contribute to the development of selective transport modulators.