Amiodarone reduces depolarization-evoked glutamate release from hippocampual synaptosomes

Decreased brain glutamate level has emerged as a new therapeutic approach for epilepsy. this study investigated the effect and mechanism of amiodarone,an anti-arrhythmic drug with antiepileptic activity,on glutamate release in the rat hippocampus. in a synaptosomal preparation,amiodarone reduced 4-aminopyridine-evoked ca2+-dependent glutamate release and cytosolic ca2+ concentration elevation. amiodarone did not affect the 4-aminopyridine-evoked depolarization of the synaptosomal membrane potential or the na+ channel activator veratridine-evoked glutamate release,indicating that the amiodarone-mediated inhibition of glutamate release is not caused by a decrease in synaptosomal excitability. the inhibitory effect of amiodarone on 4-aminopyridine-evoked glutamate release was markedly decreased in synaptosomes pretreated with the cav2.2 (n-type) and cav2.1 (p/q-type) channel blocker ω-conotoxin mviic,the calmodulin antagonists w7 and calmidazolium,or the protein kinase a inhibitors h89 and kt5720. however,the intracellular ca2+-release inhibitors dantrolene and cgp37157 had no effect on the amiodarone-mediated inhibition of glutamate release. furthermore,amiodarone reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. our data suggest that amiodarone reduces ca2+ influx through n- and p/q-type ca2+ channels,subsequently reducing the ca2+-calmodulin/protein kinase a cascade to inhibit the evoked glutamate release from rat hippocampal nerve terminals. © 2017 the authors