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

Abstract

Purpose [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-HT 3 receptor), in a cisplatin-induced pica model of rats. Methods 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-HT 3 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-HT 3 receptor, TPH and MAO-A in the medulla oblongata and ileum were measured by Western blotting and immunohistochemistry, respectively. Results [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-HT 3 receptor are important in 5-HT metabolism, and cisplatin-induced alterations in the associated protein/mRNA levels were restored when treated with [6]-gingerol. Conclusion 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-HT 3 receptor system.

Administration of a Probiotic Mixture Ameliorates Cisplatin-Induced Mucositis and Pica by Regulating 5-HT in Rats

“…Cisplatin causes both acute and delayed GI tract disorders (<24 and >24 hours after administration, respectively) [32]. Our results are consistent with those of prior studies in which cisplatin caused significant mucositis and pica in rats [8,[33][34][35]. Another study revealed that treatment with the probiotic mixture used in our study (Bifidobacterium brevis DM8310, Lactobacillus acidophilus DM8302, Lactobacillus casei DM8121, and Streptococcus thermophilus DM8309) alleviates 5-fluorouracil-induced mucositis in rats [26].…”

“…A preliminary study revealed that cisplatin significantly increased TPH1 mRNA expression, but not TPH2 and SERT mRNA expression, in ileal tissue [51]. Another study demonstrated that cisplatin increased TPH1 and TPH2 mRNA expression in the ileum and medulla oblongata, respectively, indicating that cisplatin accelerates 5-HT synthesis through upregulating TPH, but has no effect on SERT [34]. We found that cisplatin significantly increased TPH1 and TPH2 levels in the colon but did not affect the SERT level.…”

The mechanism of intestinal flora dysregulation mediated by intestinal bacterial biofilm to induce constipation

“…The neurotransmitter 5-HT is an important cholinergic transmitter secreted and synthesized by the chromaffin cells of the intestinal mucosa. It can improve intestinal permeability, increase intestinal osmotic pressure, increase water secretion, and promote intestinal peristalsis to play an important role in regulating gastrointestinal motility and gastrointestinal secretion function [ 14 ]. Studies have shown that the 5-HT transmission pathway is the key factor in the pathogenesis of chronic constipation [ 15 ].…”

Research Progress on the Antiemetic Effect of Traditional Chinese Medicine Against Chemotherapy-Induced Nausea and Vomiting: A Review

“…To better evaluate the antiemetic mechanism of ginger, the major monomer 6-gingerol is used as an approach in a cisplatin-induced pica model of rats. It was found that pretreatment with 6-gingerol significantly mitigated CINV through downregulating the synthesis and promoting the metabolism of 5-HT, as well as blocking 5-HT 3 R ( Cheng et al, 2020 ). Moreover, 6-gingerol also ameliorated microbiota disorders to alleviate cisplatin-induced kaolin intake in the pica model of rats, regulated gastrointestinal hormones, and promoted gastric emptying ( Feng et al, 2019 ; Zhang et al, 2021 ).…”

“…On one hand, unlike chemical drugs that only intervene in a single target, TCM has multiple components and interacts with multiple targets in treating diseases. For example, ginger and its active ingredients like gingerols are shown to prominently exert antiemetic effect by blocking 5-HT 3 R, NK-1R, and D 2 R as well as regulating gastrointestinal dysfunction ( Cheng et al, 2020 ; Tian et al, 2020 ). On the other hand, combining Xiao-Ban-Xia decoction (XBXD) and the 5-HT 3 R antagonist as the prophylaxis of CINV clinically not only increases the antiemetic efficacy on delayed vomiting but also reduces the adverse reactions of the 5-HT 3 R antagonist ( Ouyang et al, 2002 ; Liu, 2018 ).…”