Indole-3-carbinol (I3C), found in cruciferous vegetables, has been proposed to exhibit neuroprotective effects. This study aimed to investigate the effect of the I3C derivative [1(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (CIM), which has superior pharmacokinetic properties to I3C, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). We observed that CIM dose-dependently inhibited glutamate release evoked by the potassium channel blocker 4-aminopyridine (4-AP). CIM-mediated inhibition of glutamate release was attributed to reduced exocytosis, as it correlated with the removal of extracellular calcium and blocking of the vesicular glutamate transporter but not the glutamate transporter. In addition, CIM decreased 4-AP-evoked intrasynaptosomal Ca²⁺ elevation; however, it did not alter the synaptosomal membrane potential. The inhibition of P/Q-typeCa²⁺ channels abolished the effect of CIM on 4-AP-evoked glutamate release, and the effect was not prevented by intracellular Ca²⁺ release inhibitors. Moreover, the molecular docking study showed that CIM exhibited the highest binding affinity with the P/Q-type Ca²⁺channels. Finally, the CIM-mediated inhibition of glutamate release was sensitive to calmodulin, adenylate cyclase (AC), and protein kinase A (PKA) inhibitors. Based on these results, we propose that CIM, through the direct suppression of P/Q-type Ca²⁺ channels, decreases Ca²⁺ influx and the activation of Ca²⁺/calmodulin/AC/PKA signaling, thereby inhibiting glutamate release. This finding is crucial for understanding the role of CIM in the central nervous system and for exploiting its potential in therapeutic interventions.

在十字花科蔬菜中发现的 Indole-3-carbinol (I3C) 被认为具有神经保护作用。本研究旨在研究具有优于 I3C 的药代动力学特性的 I3C 衍生物 [1(4-氯-3-硝基苯磺酰基)-1H-吲哚-3-基]-甲醇 (CIM) 对大鼠谷氨酸盐释放的影响脑皮质神经末梢（突触体）。我们观察到 CIM 剂量依赖性地抑制由钾通道阻滞剂 4-氨基吡啶 (4-AP) 引起的谷氨酸释放。CIM 介导的谷氨酸释放抑制归因于胞吐作用减少，因为它与细胞外钙的去除和囊泡谷氨酸转运蛋白的阻断有关，但与谷氨酸转运蛋白无关。此外，CIM 降低了 4-AP 诱发的突触内 Ca ²⁺海拔; 然而，它并没有改变突触体膜电位。P/Q-typeCa ²⁺通道的抑制消除了CIM对4-AP诱发的谷氨酸释放的影响，并且细胞内Ca ²⁺释放抑制剂没有阻止该作用。此外，分子对接研究表明，CIM 与 P/Q 型 Ca ²⁺通道的结合亲和力最高。最后，CIM 介导的谷氨酸释放抑制对钙调蛋白、腺苷酸环化酶 (AC) 和蛋白激酶 A (PKA) 抑制剂敏感。基于这些结果，我们提议CIM，通过直接抑制P / Q型钙²⁺通道，减少钙²⁺内流和Ca的激活²⁺/calmodulin/AC/PKA 信号，从而抑制谷氨酸释放。这一发现对于理解 CIM 在中枢神经系统中的作用以及利用其在治疗干预中的潜力至关重要。