Presynaptic mechanisms underlying the α-lipoic acid facilitation of glutamate exocytosis in rat cerebral cortex nerve terminals

The antioxidant α-lipoic acid has been reported to prevent and reverse age-related impairments in learning and memory. However, it is unclear how α-lipoic acid improves cognitive function. In this study, the effect of α-lipoic acid on the release of endogenous glutamate from rat cerebrocortical nerve terminals (synaptosomes) was examined. We found that α-lipoic acid potently facilitated 4-aminopyridine (4AP)-evoked glutamate release, and this release facilitation results from an enhancement of vesicular exocytosis and not from an increase of non-vesicular release. Examination of the effect of α-lipoic acid on cytosolic [Ca2+] revealed that the facilitation of glutamate release was associated with an increase in voltage-dependent Ca2+ influx. Consistent with this, α-lipoic acid-mediated facilitation of glutamate release was completely prevented in synaptosomes pretreated with a wide spectrum blocker of the N- and P/Q-type Ca2+ channels, ω-conotoxin MVIIC. The facilitatory effect of α-lipoic acid on Ca2+ influx was not due to an increase of synaptosomal excitability because α-lipoic acid did not alter the 4AP-evoked depolarization of the synaptosomal plasma membrane potential. In addition, both ionomycin and hypertonic sucrose-induced glutamate release were enhanced by α-lipoic acid. Furthermore, disruption of cytoskeleton organization with cytochalasin D occluded the facilitatory effect of α-lipoic acid on 4AP or ionomycin-evoked glutamate release. These results suggest that the antioxidant α-lipoic acid enhances the Ca2+ entry through presynaptic N- and P/Q-type Ca2+ channels as well as the vesicular release machinery to cause an increase in evoked glutamate release from rat cerebrocortical synaptosomes. Also, activation of PKA and PKC may underlie, at least in part, the α-lipoic acid-mediated facilitation of glutamate release observed here as α-lipoic acid-enhanced 4AP and ionomycin-evoked glutamate release were significantly attenuated by PKA and PKC inhibitors. This finding may provide some information regarding the mechanism of action of α-lipoic acid in the central nervous system (CNS).