Quercetin inhibits depolarization-evoked glutamate release in nerve terminals from rat cerebral cortex

• Quercetin inhibited glutamate release from rat cerebrocortical synaptosomes.
• A decrease in the Ca2+ influx through Cav2.2 and Cav2.1 channels was involved.
• A role for the PKA/PKC pathway in the action of quercetin was suggested.
• This study provided further understanding of the mode of quercetin action in the brain.

Quercetin, a naturally occurring flavonoid, has been reported to have a neuroprotective profile. An excessive release of glutamate is widely considered to be one of the molecular mechanisms of neuronal damage in several neurological diseases. This study investigated whether quercetin affected glutamate release in rat cerebral cortex nerve terminals (synaptosomes) and explored the possible mechanism. Quercetin inhibited the release of glutamate evoked by the K+ channel blocker 4-aminopyridine (4-AP), and this effect was prevented by the chelating extracellular Ca2+ ions. Quercetin decreased the depolarization-induced increase in the cytosolic free Ca2+ concentration ([Ca2+]C), whereas it did not alter 4-AP-mediated depolarization and Na+ influx. The quercetin-mediated inhibition of glutamate release was prevented by blocking the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but not by blocking intracellular Ca2+ release. Combined inhibition of protein kinase C (PKC) and protein kinase A (PKA) also prevented the inhibitory effect of quercetin on evoked glutamate release. Furthermore, quercetin decreased the 4-AP-induced phosphorylation of PKC and PKA. These results suggest that quercetin inhibits glutamate release from rat cortical synaptosomes and this effect is linked to a decrease in presynaptic voltage-dependent Ca2+ entry and to the suppression of PKC and PKA activity.