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 [Ca(2+)](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 [Ca(2+)](i) and current responses induced by 100 microM applications of both kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). These responses were dependent on external Ca(2+) and were blocked by the voltage-dependent Ca(2+) channel blockers Ni(2+) and Cd(2+) . 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 (IC(50) 7 microM and 0.7 microM) of kainate stimulations. After AMPA stimulation, dose-response inhibition curves showed an IC(50) of 3 microM for CNQX and 25 microM 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.
INSERM, U 583, Institut des Neurosciences de Montpellier, Hôpital St Eloi, 80 rue Augustin Fliche, F-34091, Montpellier cedex 5, France.
Govindan
G
Dayanithi
Gilles
G
Desmadryl
Cécile
C
Travo
Christian
C
Chabbert
Alain
A
Sans
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002413:Cations, Divalent; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005456:Fluorescent Dyes; D016257:Fura-2; D017950:Ganglia, Sensory / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014722:Vestibule, Labyrinth / Q000294:innervation*
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D002118:Calcium; D002121:Calcium Channel Blockers; D002413:Cations, Divalent; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D016257:Fura-2; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D014292:Trimetazidine; D014665:Vasodilator Agents