Amiodarone reduces depolarization-evoked glutamate release from hippocampual synaptosomes

• Published in: Journal of pharmacological sciences 2017-03, Vol.133 (3), p.168-175
• Main Authors: Chang, Chia Yu, Hung, Chi Feng, Huang, Shu Kuei, Kuo, Jinn Rung, Wang, Su Jane
• Format: Article
• Language: English
• Subjects: 4-Aminopyridine - pharmacology; Amiodarone; Amiodarone - pharmacology; Animals; Anti-Arrhythmia Agents - pharmacology; Aspartic Acid - pharmacology; Ca2+ channels; Calcium - physiology; Calcium Channel Blockers - pharmacology; Calmodulin - antagonists & inhibitors; Capsaicin - pharmacology; Carbazoles - pharmacology; Glutamate release; Glutamic Acid - metabolism; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiology; Imidazoles - pharmacology; Isoquinolines - pharmacology; Macrolides - pharmacology; Male; Membrane Potentials - drug effects; omega-Conotoxins - pharmacology; Protein Kinase Inhibitors - pharmacology; Pyrroles - pharmacology; Rats, Sprague-Dawley; Sulfonamides - pharmacology; Synaptosomes; Synaptosomes - drug effects; Synaptosomes - metabolism; Synaptosomes - physiology
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2017.02.014

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.