Zeng Xiangchang, Hu Kai, Chen Lulu, Zhou Luping, Luo Wei, Li Chaopeng, Zong Wenjing, Chen Siyu, Gao Qing, Zeng Guirong, Jiang Dejian, Li Xiaohui, Zhou Honghao, Ouyang Dong-Sheng
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Central South University, Changsha, China.
Front Pharmacol. 2018 Sep 11;9:1020. doi: 10.3389/fphar.2018.01020. eCollection 2018.
The imbalance between the GABA-mediated inhibition and the glutamate-mediated excitation is the primary pathological mechanism of epilepsy. GABAergic and glutamatergic neurotransmission have become the most important targets for controlling epilepsy. Ginsenoside compound K (GCK) is a main metabolic production of the ginsenoside Rb1, Rb2, and Rc in the intestinal microbiota. Previous studies show that GCK promoted the release of GABA from the hippocampal neurons and enhanced the activity of GABA receptors. GCK is shown to reduce the expression of NMDAR and to attenuate the function of the NMDA receptors in the brain. The anti-seizure effects of GCK have not been reported so far. Therefore, this study aimed to investigate the effects of GCK on epilepsy and its potential mechanism. The rat model of seizure or status epilepticus (SE) was established with either Pentylenetetrazole or Lithium chloride-pilocarpine. The Racine's scale was used to evaluate seizure activity. The levels of the amino acid neurotransmitters were detected in the pilocarpine-induced epileptic rats. The expression levels of GABARα1, NMDAR1, KCC2, and NKCC1 protein in the hippocampus were determined via western blot or immunohistochemistry after SE. We found that GCK had deceased seizure intensity and prolonged the latency of seizures. GCK increased the contents of GABA, while the contents of glutamate remained unchanged. GCK enhanced the expression of GABARα1 in the brain and exhibited a tendency to decrease the expression of NMDAR1 protein in the hippocampus. The expression of KCC2 protein was elevated by the treatment of GCK after SE, while the expression of NKCC1 protein was reversely down-regulated. These findings suggested that GCK exerted anti-epileptic effects by promoting the hippocampal GABA release and enhancing the GABAR-mediated inhibitory synaptic transmission.
γ-氨基丁酸（GABA）介导的抑制作用与谷氨酸介导的兴奋作用之间的失衡是癫痫的主要病理机制。GABA能和谷氨酸能神经传递已成为控制癫痫的最重要靶点。人参皂苷Compound K（GCK）是人参皂苷Rb1、Rb2和Rc在肠道微生物群中的主要代谢产物。先前的研究表明，GCK促进海马神经元释放GABA，并增强GABA受体的活性。GCK被证明可降低NMDAR的表达并减弱大脑中NMDA受体的功能。迄今为止，尚未报道GCK的抗癫痫作用。因此，本研究旨在探讨GCK对癫痫的影响及其潜在机制。采用戊四氮或氯化锂-匹罗卡品建立癫痫发作或癫痫持续状态（SE）大鼠模型。使用拉辛量表评估癫痫发作活动。检测匹罗卡品诱导的癫痫大鼠中氨基酸神经递质的水平。在SE后，通过蛋白质免疫印迹法或免疫组织化学法测定海马中GABARα1、NMDAR1、KCC2和NKCC1蛋白的表达水平。我们发现，GCK降低了癫痫发作强度并延长了癫痫发作的潜伏期。GCK增加了GABA的含量，而谷氨酸的含量保持不变。GCK增强了大脑中GABARα1的表达，并呈现出海马中NMDAR1蛋白表达降低的趋势。SE后，GCK处理使KCC2蛋白的表达升高，而NKCC1蛋白的表达则反向下调。这些发现表明，GCK通过促进海马GABA释放和增强GABAR介导的抑制性突触传递发挥抗癫痫作用。
