Modulation of AMPA receptors in spinal motor neurons by the neuroprotective agent riluzole.

Abstract

We investigated the interaction of riluzole, a therapeutic agent used in amyotrophic lateral sclerosis (ALS), with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor channels in mouse spinal motor neurons in culture using whole-cell patch-clamp recording techniques. Kainate elicited concentration-dependent (EC(50) = 35 microM) inward currents in all the patched cells. These responses were mediated primarily through the activation of AMPA receptors with a negligible contribution from kainate receptors, because bath application of 100 microM GYKI53655, a potent noncompetitive AMPA receptor antagonist, completely blocked the kainate-induced currents. Riluzole (0.5-100 microM) reduced in a dose-dependent manner the kainate-induced currents with an IC(50) of 1.54 microM in all tested neurons (n = 25) and this effect was found to be reversible. The response to kainate decreased in the presence of 1 microM riluzole in all spinal motor neurons tested, without changing its EC(50), indicating a noncompetitive mechanism of inhibition. The amplitude of the responses induced by kainate under control condition and during riluzole was a linear function of the membrane potential. The reversal potential of the current was not significantly different in the two experimental conditions, whereas the total conductance of the motor neurons for the currents induced by 100 microM kainate was reduced significantly in the presence of 1 microM riluzole (P < 0.05). These results reveal an interaction of riluzole with glutamatergic neurotransmission in spinal cord motor neurons and can contribute to explain its beneficial effect in the ALS treatment.