Department of Anesthesiology, Far-Eastern Memorial Hospital, Pan-Chiao District, New Taipei City 22060, Taiwan.
Department of Mechanical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan.
Biomolecules. 2021 Oct 18;11(10):1537. doi: 10.3390/biom11101537.
Reduction in glutamate release is a key mechanism for neuroprotection and we investigated the effect of isoliquiritigenin (ISL), an active ingredient of Glycyrrhiza with neuroprotective activities, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). ISL produced a concentration-dependent inhibition of glutamate release and reduced the intraterminal [Ca] increase. The inhibition of glutamate release by ISL was prevented after removing extracellular Ca or blocking P/Q-type Ca channels. This inhibition was mediated through the γ-aminobutyric acid type B (GABA) receptors because ISL was unable to inhibit glutamate release in the presence of baclofen (an GABA agonist) or CGP3548 (an GABA antagonist) and docking data revealed that ISL interacted with GABA receptors. Furthermore, the ISL inhibition of glutamate release was abolished through the inhibition of G-mediated responses or G subunits, but not by 8-bromoadenosine 3',5'-cyclic monophosphate or adenylate cyclase inhibition. The ISL inhibition of glutamate release was also abolished through the inhibition of protein kinase C (PKC), and ISL decreased the phosphorylation of PKC. Thus, we inferred that ISL, through GABA receptor activation and G-coupled inhibition of P/Q-type Ca channels, suppressed the PKC phosphorylation to cause a decrease in evoked glutamate release at rat cerebrocortical nerve terminals.
谷氨酸释放的减少是神经保护的关键机制，我们研究了具有神经保护活性的甘草活性成分异甘草素（ISL）对大鼠脑皮质神经末梢（突触体）中谷氨酸释放的影响。ISL 产生浓度依赖性的谷氨酸释放抑制作用，并降低了末梢内 [Ca] 的增加。在去除细胞外 Ca 或阻断 P/Q 型 Ca 通道后，ISL 对谷氨酸释放的抑制作用被阻止。这种抑制是通过 γ-氨基丁酸 B 型（GABA）受体介导的，因为在巴氯芬（GABA 激动剂）或 CGP3548（GABA 拮抗剂）存在的情况下，ISL 无法抑制谷氨酸释放，并且对接数据表明 ISL 与 GABA 受体相互作用。此外，通过抑制 G 介导的反应或 G 亚基，ISL 对谷氨酸释放的抑制作用被消除，但通过 8-溴腺苷 3'，5'-环单磷酸或腺苷酸环化酶抑制则不能消除。ISL 对谷氨酸释放的抑制作用也通过抑制蛋白激酶 C（PKC）而被消除，并且 ISL 降低了 PKC 的磷酸化。因此，我们推断 ISL 通过 GABA 受体激活和 G 偶联抑制 P/Q 型 Ca 通道，抑制 PKC 磷酸化，从而导致大鼠脑皮质神经末梢诱发的谷氨酸释放减少。
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