kt-5720 and idebenone

The present study was aimed at investigating the effect and the possible mechanism of idebenone on endogenous glutamate release in nerve terminals of rat cerebral cortex (synaptosomes). Idebenone inhibited the release of glutamate that was evoked by exposing synaptosomes to the K(+) channel blocker 4-aminopyridine (4-AP), and this phenomenon was concentration dependent. Inhibition of glutamate release by idebenone was prevented by chelating extracellular Ca(2+), or by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to DL-threo-beta-benzyl-oxyaspartate, a glutamate transporter inhibitor. Idebenone decreased the depolarization-induced increase in the cytosolic free Ca(2+) concentration ([Ca(2+)](C)),whereas it did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization. The inhibitory effect of idebenone on evoked glutamate release was prevented by blocking the Ca(v)2.2 (N-type) and Ca(v)2.1 (P/Q-type) channels, but not by blocking intracellular Ca(2+) release or Na(+)/Ca(2+) exchange. Furthermore, the idebenone effect on 4-AP-evoked Ca(2+) influx and glutamate release was completely abolished by the protein kinase A (PKA) inhibitors, H89 and KT5720. On the basis of these results, it was concluded that idebenone inhibits glutamate release from rat cortical synaptosomes and this effect is linked to a decrease in [Ca(2+)](C) contributed by Ca(2+) entry through presynaptic voltage-dependent Ca(2+) channels and to the suppression of PKA signaling cascade.

Topics: 4-Aminopyridine; Animals; Aspartic Acid; Calcium; Calcium Channel Blockers; Calcium Channels; Calcium Signaling; Carbazoles; Cerebral Cortex; Clonazepam; Cyclic AMP-Dependent Protein Kinases; Dantrolene; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glutamate Plasma Membrane Transport Proteins; Glutamic Acid; Indoles; Isoquinolines; Macrolides; Male; Maleimides; Membrane Potentials; Nerve Endings; omega-Conotoxins; Potassium; Protein Kinase C; Protein Kinase Inhibitors; Pyrroles; Rats; Rats, Sprague-Dawley; Sodium-Calcium Exchanger; Sulfonamides; Synaptosomes; Thiazepines; Ubiquinone