<p>[6]-Gingerol Ameliorates Cisplatin-Induced Pica by Regulating the TPH/MAO-A/SERT/5-HT/5-HT<sub>3</sub> Receptor System in Rats</p>
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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. Keywords: [6]-gingerol, serotonin, cisplatin, pica, ratsKeywords:
Ondansetron
5-HT3 receptor
5-Hydroxyindoleacetic acid
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The object of this study was to evaluate the involvement of 5-HT3 receptors in the regulation of 5-HT release from the small intestine using ferrets, an animal model of emesis. 2-Methyl-5-HT, a 5-HT3 receptor agonist, produced a concentration-dependent increase of 5-HT from the ferret ileum. This increase in 5-HT release was significantly inhibited by granisetron (10(-7) and 10(-6) M) or azasetron (10(-7) and 10(-6) M) in a concentration-dependent manner. Ondansetron (10(-7) M) and ramosetron (10(-6) M) also significantly inhibited the 2-methyl-5-HT-induced increase in 5-HT release. When the concentration of ondansetron was increased from 10(-7) M to 10(-6) M, inhibition of 5-HT release was reduced. Ramosetron, for which 5-HT3 receptor binding of the rat brain is remarkably stronger than for any other 5-HT3 receptor antagonists, inhibited the 5-HT release at only the highest concentration of 10(-6) M. Based on these observations that the mode of action on the 2-methyl-5-HT induced 5-HT release is different among 5-HT3 receptor antagonists, it is suggested that there is a possibility that the neuronal 5-HT3 receptors and the 5-HT3 receptors on the EC cells may represent two distinct subtypes.
5-HT3 receptor
Granisetron
Ondansetron
Enterochromaffin cell
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Employing C14-glucose and C14-serotonin (5HT) as precursors, we have synthesized desoxyfructo-5HT [1-desoxy-1-(5-hydroxytryptamine)-D-fructose] labelled either in the sugar or 5HT moieties, and examined the uptake of the labelled substrate by washed human platelets. Desoxyfructo-5HT appears to interact with the 5HT uptake site, effectively inhibiting the uptake of H3-5HT. However, our data indicate that contrary to published reports, the entry of desoxyfructo-5HT into platelet vesicles or cytoplasm is negligible.
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SUMMARY The cardiovascular actions of serotonin and its antagonists are reviewed with a view to clarifying whether serotonin has a role in blood pressure control through actions on the peripheral vasculature. Serotonin has complex actions in the heart and vasculature but none of these actions is completely understood. There is no doubt, however, that serotonin has extensive interactions with the sympathetic nervous system. The nature of the serotonin receptor is also discussed. There is extensive evidence that more than one type of serotonin receptor exists. Biochemical studies in brain homogenates have delineated two sub‐populations of serotonin receptors, named 5HT 1 and 5HT 2 . It is not clear whether the same receptor types exist in the vasculature but various actions of serotonin on the vasculature have tentatively been ascribed to actions on 5HT 1 ‐ and 5HT 2 ‐type receptors. It is clear that there is some functional overlap between serotonin‐receptors and α‐adrenoceptors. The mechanism by which this overlap could occur is unknown although we suggest it may result from a physical overlap of serotonin receptors and α‐adrenoceptors. Compounds which antagonize serotonin have provided the means for investigating serotonin receptors but have not clarified the role of serotonin in blood pressure control; certainly they have comparatively little effect on blood pressure and this may simply reflect the lack of free circulating serotonin. In animal studies the new serotonin antagonist ketanserin appears to lower blood pressure via α‐adrenoceptor blockade.
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Serotonin Antagonists
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Abstract This unit describes assays for measuring the binding of radioligands to two major types of receptors for 5‐hydroxytryptamine (5‐HT or serotonin), 5‐HT 1 and 5‐HT 2 receptors, in homogenates of brain tissue or cloned into cells in culture. The specific receptor subtypes covered are 5‐HT 1A , 5‐HT 1B , 5‐HT 2A , and 5‐HT 2C . In addition, methodology for using quantitative autoradiography to measure radioligand binding to serotonin receptors in brain slices is described. Protocols are provided for characterization of both saturation and competition binding assays, and instructions for data analysis of these assays is also described. In addition, methodology is provided for the quantification (image analysis) of radioligand binding in brain tissue sections to determine receptor density, preparation of rat brain sections for quantitative autoradiography, and thionin staining of thaw‐mounted tissue sections to define certain brain regions.
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Radioligand Assay
Ligand binding assay
5-HT1 receptor
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Employing C14-glucose and C14-serotonin (5HT) as precursors, we have synthesized desoxyfructo-5HT [1-desoxy-1-(5-hydroxytryptamine)-D-fructose] labelled either in the sugar or 5HT moieties, and examined the uptake of the labelled substrate by washed human platelets. Desoxyfructo-5HT appears to interact with the 5HT uptake site, effectively inhibiting the uptake of H3-5HT. However, our data indicate that contrary to published reports, the entry of desoxyfructo-5HT into platelet vesicles or cytoplasm is negligible.
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5-HT2 receptor
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Serotonin (5-hydroxytryptamine; 5-HT) performs a variety of functions in the body including the modulation of muscle tone in respiratory airways. Several studies indicate a possible role of 5-HT in the pathophysiology of bronchial hyperresponsiveness. However, the receptors and the molecular mechanisms by which 5-HT acts on airway smooth muscle (ASM) continue to be controversial. Most of the evidence suggests the participation of different subtypes of receptors in an indirect response. This study supports the proposal that 5-HT directly contracts ASM and characterizes pharmacologically the subtypes of serotonergic receptors involved. The characterization was carried out by using selective antagonists in an organ bath model allowing study of the smooth muscle of segments of bovine trachea.The results obtained show that 5-HT2A receptors are the main mediators of the direct contractile response of bovine ASM, with the cooperation of the 5-HT7, 5-HT3 and 5-HT1B/D receptors. Also, it was observed that the muscle response to serotonin is developed more slowly and to a lesser extent in comparison with the response to cholinergic stimulation.Overall, the receptors that mediate the direct serotonergic contraction of the smooth muscle of the bovine trachea are 5-HT2A, 5-HT7, 5-HT3 and 5-HT1B/D receptors.
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A series of photolabile o-nitrobenzyl derivatives of serotonin (caged serotonin) were synthesized: the amine-linked serotonin derivatives N-(2-nitrobenzyl) serotonin (Bz-5HT) and N-(alpha-carboxy-2-nitrobenzyl) serotonin (N-CNB-5HT), and O-alpha-carboxy-2-nitrobenzyl) serotonin (O-CNB-5HT), which has the caging group attached to the phenolic OH group. All the derivatives released free serotonin when excited by 308-nm or 337-nm laser pulses. The time constant of serotonin release from N-CNB-5HT was 1. 2 ms, with a quantum yield of 0.08. This is too slow for rapid chemical kinetic measurements. O-CNB-5HT is suitable for transient kinetic investigations of the serotonin 5-HT(3) receptor. It released serotonin with a time constant of 16 micros and a quantum yield of 0.03. The biological properties of O-CNB-5HT were evaluated, and the applicability of the compound for kinetic studies of the 5-HT(3) receptor was demonstrated. O-CNB-5HT does not activate the 5-HT(3) receptor by itself, nor does it modulate the response of a cell when co-applied with serotonin. When irradiated with a 337-nm laser pulse, O-CNB-5HT released free serotonin that evoked 5-HT(3) receptor-mediated whole-cell currents in NIE-115 mouse neuroblastoma cells.
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