Trimetazidine modulates AMPA/kainate receptors in rat vestibular ganglion neurons

Trimetazidine (1[2,3,4-trimethoxy-benzyl] piperazine, 2 HCl) is an anti-ischemic agent frequently administered as a prophylactic treatment for episodes of angina pectoris and chorioretinal disturbances. It is also employed as a symptomatic treatment of vertigo but its mechanism of action is yet to be defined. Using Fura-2 fluorescence photometry and whole-cell patch-clamp recordings we investigated the effect of trimetazidine on the [Ca2+]i and current responses induced by the application of non-N-methyl-d-aspartate (NMDA) receptor agonists on low density vestibular ganglion neuronal cultures explanted from 3 day s postnatal rats. Trimetazidine blocked the [Ca2+]i and current responses induced by 100 μM applications of both kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). These responses were dependent on external Ca2+ and were blocked by the voltage-dependent Ca2+ channel blockers Ni2+ and Cd2+ . Trimetazidine only acts on the AMPA/kainate receptors and had no effect on K+-induced depolarizations. Dose-dependent curves were obtained for the inhibition by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and trimetazidine (IC50 7 μM and 0.7 μM) of kainate stimulations. After AMPA stimulation, dose–response inhibition curves showed an IC50 of 3 μM for CNQX and 25 μM for trimetazidine. These results indicate that trimetazidine could be a potent antagonist of AMPA/kainate receptors in vestibular ganglion neurons. This may explain the protective role of trimetazidine in the inner ear suggesting an anti-excitotoxic activity.