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      [6]-Gingerol Ameliorates Cisplatin-Induced Pica by Regulating the TPH/MAO-A/SERT/5-HT/5-HT 3 Receptor System in Rats

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          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.

          Most cited references32

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          Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function.

          Serotonin (5-HT) controls a wide range of biological functions. In the brain, its implication as a neurotransmitter and in the control of behavioral traits has been largely documented. At the periphery, its modulatory role in physiological processes, such as the cardiovascular function, is still poorly understood. The rate-limiting enzyme of 5-HT synthesis, tryptophan hydroxylase (TPH), is encoded by two genes, the well characterized tph1 gene and a recently identified tph2 gene. In this article, based on the study of a mutant mouse in which the tph1 gene has been inactivated by replacement with the beta-galactosidase gene, we establish that the neuronal tph2 is expressed in neurons of the raphe nuclei and of the myenteric plexus, whereas the nonneuronal tph1, as detected by beta-galactosidase expression, is in the pineal gland and the enterochromaffin cells. Anatomic examination of the mutant mice revealed larger heart sizes than in wild-type mice. Histological investigation indicates that the primary structure of the heart muscle is not affected. Hemodynamic analyses demonstrate abnormal cardiac activity, which ultimately leads to heart failure of the mutant animals. This report links loss of tph1 gene expression, and thus of peripheral 5-HT, to a cardiac dysfunction phenotype. The tph1-/- mutant may be valuable for investigating cardiovascular dysfunction observed in heart failure in humans.
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            The development of a prediction tool to identify cancer patients at high risk for chemotherapy-induced nausea and vomiting

            Background Despite the availability of effective antiemetics and evidence-based guidelines, up to 40% of cancer patients receiving chemotherapy fail to achieve complete nausea and vomiting control. In addition to type of chemotherapy, several patient-related risk factors for chemotherapy-induced nausea and vomiting (CINV) have been identified. To incorporate these factors into the optimal selection of prophylactic antiemetics, a repeated measures cycle-based model to predict the risk of ≥ grade 2 CINV (≥2 vomiting episodes or a decrease in oral intake due to nausea) from days 0 to 5 post-chemotherapy was developed. Patients and methods Data from 1198 patients enrolled in one of the five non-interventional CINV prospective studies were pooled. Generalized estimating equations were used in a backwards elimination process with the P-value set at <0.05 to identify the relevant predictive factors. A risk scoring algorithm (range 0–32) was then derived from the final model coefficients. Finally, a receiver-operating characteristic curve (ROCC) analysis was done to measure the predictive accuracy of the scoring algorithm. Results Over 4197 chemotherapy cycles, 42.2% of patients experienced ≥grade 2 CINV. Eight risk factors were identified: patient age <60 years, the first two cycles of chemotherapy, anticipatory nausea and vomiting, history of morning sickness, hours of sleep the night before chemotherapy, CINV in the prior cycle, patient self-medication with non-prescribed treatments, and the use of platinum or anthracycline-based regimens. The ROC analysis indicated good predictive accuracy with an area-under-the-curve of 0.69 (95% CI: 0.67–0.70). Before to each cycle of therapy, patients with risk scores ≥16 units would be considered at high risk for developing ≥grade 2 CINV. Conclusions The clinical application of this prediction tool will be an important source of individual patient risk information for the oncology clinician and may enhance patient care by optimizing the use of the antiemetics in a proactive manner.
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              Pica in rats is analogous to emesis: an animal model in emesis research.

              Mitchell et al. (1976, 1977) suggested that pica, eating of nonnutritive substances such as kaolin, is an illness-response behavior in rats. In the present study, we first confirmed their suggestion and then examined the effects of antiemetics on emetic-induced pica in rats. Intraperitoneal injection of apomorphine induced dose-dependent kaolin consumption. Pretreatment with domperidone inhibited apomorphine-induced kaolin intake. Oral administration of copper sulfate and intraperitoneal injection of cisplatin also induced dose-dependent kaolin consumption. Pretreatment with ondansetron inhibited cisplatin-induced kaolin intake. These findings suggest that pica in rats was induced through 1) dopamine D2 receptors in the chemoreceptor trigger zone, and 2) the stomach, partly via 5-HT3 receptors in the visceral afferents in the stomach wall. The present findings support the conclusion that pica in rats is analogous to vomiting in other species and suggest that pica in rats is mediated by the same mechanisms as vomiting in humans. Accordingly, we extended the utility of the animal model to pharmacological research of emesis with pica as an analogue to emesis.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                02 October 2020
                2020
                : 14
                : 4085-4099
                Affiliations
                [1 ]School of Chinese Materia Medica, Guangdong Pharmaceutical University , Guangzhou, Guangdong Province 510006, People’s Republic of China
                [2 ]School of Chinese Medicine, Shandong University of Traditional Chinese Medicine , Jinan, Shandong Province 250355, People’s Republic of China
                Author notes
                Correspondence: Ke Nie School of Chinese Materia Medica, Guangdong Pharmaceutical University , 280 Waihuan East Road, Panyu District, Guangzhou, Guangdong Province510006, People’s Republic of ChinaTel +86 203 935 2557 Email nicknk@hotmail.com
                Author information
                http://orcid.org/0000-0002-2916-8777
                http://orcid.org/0000-0001-7036-123X
                http://orcid.org/0000-0003-4410-7662
                Article
                270185
                10.2147/DDDT.S270185
                7538004
                a7afa266-daee-4447-b8a8-9212fc009887
                © 2020 Cheng et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 07 July 2020
                : 01 September 2020
                Page count
                Figures: 11, Tables: 1, References: 33, Pages: 15
                Funding
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                This work was supported by the National Natural Science Foundation of China; Grant number (81673779).
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                [6]-gingerol,serotonin,cisplatin,pica,rats
                Pharmacology & Pharmaceutical medicine
                [6]-gingerol, serotonin, cisplatin, pica, rats

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