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Mechanisms underlying the honokiol inhibition of evoked glutamate release from glutamatergic nerve terminals of the rat cerebral cortex

The effect of honokiol, an active component of Magnolia officinalis, on glutamate release from isolated nerve terminals (synaptosomes) was examined. Honokiol potently inhibited 4‐aminopyridine (4‐AP)‐evoked glutamate release in a concentration‐dependent manner, and this effect resulted from a reduction of vesicular exocytosis and not from an inhibition of Ca2+‐independent efflux via glutamate transporter. The inhibitory action of honokiol was not due to decreasing synaptosomal excitability or directly interfering with the release process at some point subsequent to Ca2+ influx, because honokiol did not alter the 4‐AP‐evoked depolarization of the synaptosomal plasma membrane potential or Ca2+ ionophore ionomycin‐induced glutamate release. Rather, examination of the effect of honokiol on cytosolic [Ca2+] revealed that the diminution of glutamate release could be attributed to a reduction in voltage‐dependent Ca2+ influx. Consistent with this, the honokiol‐mediated inhibition of 4‐AP‐evoked glutamate release was completely prevented in synaptosomes pretreated with a wide‐spectrum blocker of N‐, P‐, and Q‐type Ca2+ channels, ω‐conotoxin MVIIC. In addition, honokiol modulation of 4‐AP‐evoked glutamate release appeared to involve a protein kinase C (PKC) signaling cascade, in so far as pretreatment of synaptosomes with the PKC inhibitors Ro318220 or GF109203X all effectively occluded the inhibitory effect of honokiol. Furthermore, honokiol attenuated 4‐AP‐induced phosphorylation of PKC. Together, these results suggest that honokiol effects a decrease in PKC activation, which subsequently attenuates the Ca2+ entry through voltage‐dependent N‐ and P/Q‐type Ca2+ channels to cause a decrease in evoked glutamate exocytosis. These actions of honokiol may contribute to its neuroprotective effect in excitotoxic injury. Synapse 62:890–901, 2008. © 2008 Wiley‐Liss, Inc.