The Effects of Ginsenoside Compound K Against Epilepsy by Enhancing the γ-Aminobutyric Acid Signaling Pathway

Xiangchang Zeng; Kai Hu; Lulu Chen; Luping Zhou; Wei Luo; Chaopeng Li; Wenjing Zong; Siyu Chen; Qing Gao; Guirong Zeng; Dejian Jiang; Xiaohui Li; Honghao Zhou; Dong-Sheng Ouyang

doi:10.3389/fphar.2018.01020

The Effects of Ginsenoside Compound K Against Epilepsy by Enhancing the γ-Aminobutyric Acid Signaling Pathway

Front Pharmacol. 2018 Sep 11:9:1020. doi: 10.3389/fphar.2018.01020. eCollection 2018.

Authors

Xiangchang Zeng^{1

2}, Kai Hu³, Lulu Chen^{1

2}, Luping Zhou^{1

2}, Wei Luo^{1

2}, Chaopeng Li^{1

2}, Wenjing Zong^{1

2}, Siyu Chen^{1

2}, Qing Gao^{1

2}, Guirong Zeng⁴, Dejian Jiang⁴, Xiaohui Li^{5

6}, Honghao Zhou^{1

2}, Dong-Sheng Ouyang^{1

2

6}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
² Institute of Clinical Pharmacology, Central South University, Changsha, China.
³ Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
⁴ Hunan Key Laboratory of Pharmacodynamics and Safety Evaluation of New Drugs & Hunan Provincial Research Center for Safety Evaluation of Drugs, Changsha, China.
⁵ Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China.
⁶ Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd., Changsha, China.

Abstract

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_A 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 GABA_ARα1, 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 GABA_ARα1 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 GABA_AR-mediated inhibitory synaptic transmission.

Keywords: GABAARα1; KCC2; NKCC1; epilepsy; ginsenoside compound K; neurotransmitters.