Lu Cheng-Wei, Lin Tzu-Yu, Chiu Kuan-Ming, Lee Ming-Yi, Huang Jih-Hsin, Wang Su-Jane
Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei 22060, Taiwan.
Department of Mechanical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan.
Biomedicines. 2020 Nov 9;8(11):486. doi: 10.3390/biomedicines8110486.
Silymarin, a polyphenoic flavonoid derived from the seeds of milk thistle (), exhibits neuroprotective effects. In this study, we used a model of rat cerebrocortical synaptosomes to investigate whether silymarin affects the release of glutamate, an essential neurotransmitter involved in excitotoxicity. Its possible neuroprotective effect on a rat model of kainic acid (KA)-induced excitotoxicity was also investigated. In rat cortical synaptosomes, silymarin reduced glutamate release and calcium elevation evoked by the K channel blocker 4-aminopyridine but did not affect glutamate release caused by the Na channel activator veratridine or the synaptosomal membrane potential. Decreased glutamate release by silymarin was prevented by removal of extracellular calcium and blocking of N- and P/Q-type Ca channel or extracellular signal-regulated kinase 1/2 (ERK1/2) but not by blocking of intracellular Ca release. Immunoblotting assay results revealed that silymarin reduced 4-aminopyridine-induced phosphorylation of ERK1/2. Moreover, systemic treatment of rats with silymarin (50 or 100 mg/kg) 30 min before systemic KA (15 mg/kg) administration attenuated KA-induced seizures, glutamate concentration elevation, neuronal damage, glial activation, and heat shock protein 70 expression as well as upregulated KA-induced decrease in Akt phosphorylation in the rat hippocampus. Taken together, the present study demonstrated that silymarin depressed synaptosomal glutamate release by suppressing voltage-dependent Ca entry and ERK1/2 activity and effectively prevented KA-induced in vivo excitotoxicity.
水飞蓟素是一种从水飞蓟种子中提取的多酚类黄酮，具有神经保护作用。在本研究中，我们使用大鼠大脑皮质突触体模型来研究水飞蓟素是否会影响谷氨酸的释放，谷氨酸是一种与兴奋性毒性有关的重要神经递质。我们还研究了其对 kainic acid（KA）诱导的兴奋性毒性大鼠模型可能的神经保护作用。在大鼠皮质突触体中，水飞蓟素减少了由钾通道阻滞剂 4-氨基吡啶引起的谷氨酸释放和钙升高，但不影响由钠通道激活剂藜芦碱引起的谷氨酸释放或突触体膜电位。通过去除细胞外钙以及阻断 N 型和 P/Q 型钙通道或细胞外信号调节激酶 1/2（ERK1/2）可防止水飞蓟素降低谷氨酸释放，但阻断细胞内钙释放则不能。免疫印迹分析结果显示，水飞蓟素减少了 4-氨基吡啶诱导的 ERK1/2 磷酸化。此外，在全身给予 KA（15 mg/kg）前 30 分钟，用 50 或 100 mg/kg 的水飞蓟素对大鼠进行全身治疗，可减轻 KA 诱导的癫痫发作、谷氨酸浓度升高、神经元损伤、神经胶质细胞活化和热休克蛋白 70 表达，以及上调 KA 诱导的大鼠海马中 Akt 磷酸化的降低。综上所述，本研究表明水飞蓟素通过抑制电压依赖性钙内流和 ERK1/2 活性来降低突触体谷氨酸释放，并有效预防 KA 诱导的体内兴奋性毒性。
