Sy Hiu-Ngar, Wu Shey-Lin, Wang Wang-Fu, Wang Su-Jane
Department of Neurology, Changhua Christian Hospital, Changhua City, Changhua County 500, Taiwan.
Synapse. 2008 Dec;62(12):890-901. doi: 10.1002/syn.20568.
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 Ca(2+)-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 Ca(2+) influx, because honokiol did not alter the 4-AP-evoked depolarization of the synaptosomal plasma membrane potential or Ca(2+) ionophore ionomycin-induced glutamate release. Rather, examination of the effect of honokiol on cytosolic [Ca(2+)] revealed that the diminution of glutamate release could be attributed to a reduction in voltage-dependent Ca(2+) 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 Ca(2+) channels, omega-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 Ca(2+) entry through voltage-dependent N- and P/Q-type Ca(2+) channels to cause a decrease in evoked glutamate exocytosis. These actions of honokiol may contribute to its neuroprotective effect in excitotoxic injury.
研究了厚朴活性成分厚朴酚对离体神经末梢（突触体）谷氨酸释放的影响。厚朴酚能以浓度依赖的方式有效抑制4-氨基吡啶（4-AP）诱发的谷氨酸释放，这种作用是由于囊泡胞吐作用的减少，而非通过谷氨酸转运体抑制不依赖Ca(2+)的外流。厚朴酚的抑制作用并非由于降低突触体兴奋性或在Ca(2+)内流后的某个点直接干扰释放过程，因为厚朴酚不会改变4-AP诱发的突触体质膜电位去极化或Ca(2+)离子载体离子霉素诱导的谷氨酸释放。相反，对厚朴酚对胞质[Ca(2+)]影响的研究表明，谷氨酸释放的减少可归因于电压依赖性Ca(2+)内流的减少。与此一致的是，在用N-、P-和Q型Ca(2+)通道的广谱阻滞剂ω-芋螺毒素MVIIC预处理的突触体中，厚朴酚介导的对4-AP诱发的谷氨酸释放的抑制作用被完全阻断。此外，就突触体用蛋白激酶C（PKC）抑制剂Ro318220或GF109203X预处理均有效阻断厚朴酚的抑制作用而言，厚朴酚对4-AP诱发的谷氨酸释放的调节似乎涉及PKC信号级联反应。此外，厚朴酚减弱了4-AP诱导的PKC磷酸化。总之，这些结果表明厚朴酚导致PKC激活的减少，随后减弱通过电压依赖性N-和P/Q型Ca(2+)通道的Ca(2+)内流，从而导致诱发的谷氨酸胞吐作用减少。厚朴酚的这些作用可能有助于其在兴奋性毒性损伤中的神经保护作用。
