Antimania-Like Effect of Panax ginseng Regulating the Glutamatergic Neurotransmission in REM-Sleep Deprivation Rats

Abstract

Previous studies have shown the therapeutic properties of ginseng and ginsenosides on hyperactive and impulsive behaviors in several psychiatric diseases. Herein, we investigated the effect of Panax ginseng Meyer (PG) on hyperactive/impulsive behaviors in a manic-like animal model, sleep deprivation (SD) rats. Male rats were sleep-deprived for 48 h, and PG (200 mg/kg) was administered for 4 days, from 2 days prior to the start of SD to the end date of SD. The elevated plus maze (EPM) test showed that PG alleviated the increased frequency of entries into and spent time within open arms by SD. In order to investigate the molecular mechanism on this effect of PG, we assessed differentially expressed genes (DEGs) in the prefrontal cortex of PG-treated SD rats using RNA sequencing (RNA-seq) and performed gene-enrichment analysis for DEGs. The gene-enrichment analysis showed that PG most prominently affected the glutamatergic synapse pathway. Among the glutamatergic synapse pathway genes, particularly, PG enhanced the expressions of glutamate transporter Slc1a3 and Slc1a2 reduced in SD rats. Moreover, we found that PG could inhibit the SD-induced phosphorylation of the NR2A subunit of the NMDA receptor. These results suggested that PG might have a therapeutic effect against the manic-like behaviors, regulating the glutamatergic neurotransmission.

Figure 1

Effects of Panax ginseng (PG) on manic-like behaviors in sleep deprivation (SD) rats. Manic-like behaviors in sleep deprivation rats were measured using the elevated plus-maze (EPM) test. Impulsive behavior was indicated by (a) the percentage of open arm entries and (b) percentage of time spent in the open arms. (c) Hyperactive locomotion was indicated by the number of total entries into the open and closed arms. The results are presented as the mean ± SE of two independent experiments (n = 4 for each group per each experiment). ^∗p < 0.05 compared to the control group; ^†p < 0.05 compared to the SD group. PG, PG.

Figure 2

Quantitative real-time PCR (qRT-PCR) validation of the glutamatergic synapse and amphetamine addiction pathway genes. Expressions of the glutamatergic synapse and amphetamine addiction pathway genes were determined using the qRT-PCR in the prefrontal cortex of the control, sleep deprivation (SD), and Panax ginseng (PG)-treated SD rats. The histogram reveals the expression levels of genes as mean ± SE. Expression levels were normalized against ubiquitin C (Ubc). The experiments were repeated in duplicates (n = 4 for each group per experiment). ^∗p < 0.05 compared to the control group; ^†p < 0.05 compared to the SD group.

Figure 3

Effect of Panax ginseng (PG) on the expression of Slc1a2, Slc1A3, and Arc and the phosphorylation of the NMDA receptor in sleep deprivation (SD) rats. (a) The expressions of Slc1a2, Slc1A3, and Arc and (b) the phosphorylations of the NR2 subunits of the NMDA receptor were determined using immunoblotting in the prefrontal cortex of the control, SD, and PG-treated SD rats. The left and middle histograms represent the protein expression and the phosphorylation levels divided by the expression level of β-actin as mean ± SE. The right histogram shows the ratio of the phosphorylation levels to the protein expression levels. β-Actin expression was used as an internal control. The experiments were repeated in duplicates (n = 3 for each group per experiment). ^∗p < 0.05 compared to the control group; ^†p < 0.05 compared to the SD group.