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

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

Xiangchang Zeng  1   2 , Kai Hu  3 , 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 Zeng  4 , Dejian Jiang  4 , Xiaohui Li  5   6 , Honghao Zhou  1   2 , Dong-Sheng Ouyang  1   2   6
Affiliations

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

Xiangchang Zeng et al. Front Pharmacol. .

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 GABAA 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 GABAARα1, 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 GABAARα1 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 GABAAR-mediated inhibitory synaptic transmission.

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

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Figures

FIGURE 1
FIGURE 1
Effects of GCK on behavioral seizures induced by pentylenetetrazole (PTZ). (A) The seizure scores of the PTZ, VPA, and GCK-treated groups. (B) The latency to clonic seizures in the PTZ, VPA, and GCK-treated groups. (C) The duration of the PTZ, VPA, and GCK-treated groups. Values are mean ± SEM (n = 10). PTZ 60 mg/kg, VPA 400 mg/kg, GCK 80 mg/kg, 160 mg/kg, and 320 mg/kg. Values were compared with the PTZ, ∗P < 0.05, ∗∗P < 0.01.
FIGURE 2
FIGURE 2
Effects of GCK on behavioral seizures induced by lithium chloride-pilocarpine. (A) The seizure scores of the Pilo, VPA, and GCK-treated groups. (B) The latency to onset SE in the Pilo, VPA, and GCK-treated groups. Values are mean ± SEM (n = 10). Pilo 30 mg/kg, VPA 400 mg/kg, GCK 80 mg/kg, 160 mg/kg, and 320 mg/kg. Compared with the Pilo, ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001.
FIGURE 3
FIGURE 3
Effects of GCK on the hippocampal neurotransmitters glutamate and γ-amino butyric acid (GABA) contents in pilocarpine-induced epileptic rats. (A) The contents of GABA in the Con, Pilo, VPA, and GCK-treated groups. (B) The contents of glutamate in the Con, Pilo, VPA, and GCK-treated groups. Values are mean ± SEM (n = 5). Pilo 30 mg/kg, VPA 400 mg/kg, GCK 80 mg/kg, 160 mg/kg, and 320 mg/kg. Compared with the Con ∗P < 0.05; compared with the Pilo, #P < 0.05.
FIGURE 4
FIGURE 4
Effects of GCK on the expression of GABAARα1 and NMDAR1 protein in the hippocampus of the pilocarpine-induced epileptic rats. (A) The expression of GABAARα1 in the Con, Pilo, VPA, and GCK-treated groups. (B) The expression of NMDAR1 in the Con, Pilo, VPA, and GCK-treated groups. (C–G) The GABAARα1 immunoreactivity in the hippocampal CA1, CA3, DG, and H regions. Scale bar: 100 μm. Values are mean ± SEM (n = 5). Pilo 30 mg/kg, VPA 400 mg/kg, GCK 80 mg/kg, 160 mg/kg, and 320 mg/kg. Compared with the Con ∗P < 0.05; Compared with the Pilo, #P < 0.05.
FIGURE 5
FIGURE 5
Effects of GCK on the expression of KCC2 and NKCC1 protein in the hippocampus of the pilocarpine-induced epileptic rats. (A) The expression of KCC2 in the Con, Pilo, VPA, and GCK-treated groups. (B) The expression of NKCC1 in the Con, Pilo, VPA, and GCK-treated groups. (C–G) The KCC2 immunoreactivity in the hippocampal CA1, CA3, DG, and H regions. Scale bar: 100 μm. (H–L) The NKCC1 immunoreactivity in the hippocampal CA1, CA3, DG, and H regions. Scale bar: 100 μm. Values are mean ± SEM (n = 5). Pilo 30 mg/kg, VPA 400 mg/kg, GCK 80 mg/kg, 160 mg/kg, and 320 mg/kg. Compared with the Con ∗P < 0.05; compared with the Pilo, #P < 0.05.
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