[6]-Gingerol Ameliorates Cisplatin-Induced Pica by Regulating the TPH/MAO-A/SERT/5-HT/5-HT₃ Receptor System in Rats

[6]-gingerol is a bioactive compound extracted from ginger, a traditional anti-emetic herb in Chinese medicine. Previous studies have demonstrated that [6]-gingerol can ameliorate chemotherapy-induced pica in rats, although the underlying mechanism has not been elucidated. This study is designed to investigate [6]-gingerol's antiemetic mechanism focusing on the 5-hydroxytryptamine (serotonin, 5-HT) system by evaluating the synthesis, metabolism and reuptake of 5-HT, as well as the mechanism of 5-hydroxytryptamine type 3 receptor (5-HT₃ receptor), in a cisplatin-induced pica model of rats.

Rats were randomly divided into control group (vehicle + saline, Con), [6]-gingerol control group (50 mg/kg [6]-gingerol + saline, G-con), ondansetron control group (2.6 mg/kg ondansetron + saline, O-con), cisplatin model group (vehicle + cisplatin, Model), ondansetron-treated group (2.6 mg/kg ondansetron + cisplatin, O-treated), high dosage of [6]-gingerol-treated group (100 mg/kg [6]-gingerol + cisplatin, GH-treated), and low dosage of [6]-gingerol-treated group (50 mg/kg [6]-gingerol + cisplatin, GL-treated). The rats were administered with [6]-gingerol, ondansetron, and vehicle (3% Tween-80) by gavage twice (7:00 AM and 7:00 PM). One hour after the first treatment (8:00 AM), rats in groups Model, O-treated, GH-treated and GL-treated were injected intraperitoneally (i.p.) with 6 mg/kg cisplatin, and the other groups were injected i.p. with saline of equal volume. The consumption of kaolin of the rats were measured. All the rats were anesthetized by i.p. injection of pentobarbital sodium at 24 h post-cisplatin. After blood samples were taken, medulla oblongata and ileum were removed. The levels of 5-HT and its metabolite 5-HIAA in ileum, medulla oblongata and serum were determined using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). The mRNA expression levels of 5-HT₃ receptor, tryptophan hydroxylase (TPH), monoamine oxidase A (MAO-A) and serotonin reuptake transporter (SERT) were detected by real-time PCR. The protein expression levels and distribution of 5-HT₃ receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively.

[6]-gingerol treatment significantly reduced the kaolin ingestion and the increase in 5-HT concentration in rats induced by cisplatin. TPH, MAO-A, SERT, and 5-HT₃ receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol.

This suggests that the antiemetic effect of [6]-gingerol against cisplatin-induced emesis may be due to 5-HT attenuation via modulating the TPH/MAO-A/SERT/5-HT/5-HT₃ receptor system.