Cisplatin-induced Kaolin Intake Research Articles

Liujunanwei decoction attenuates cisplatin-induced nausea and vomiting in a Rat-Pica model partially mediated by modulating the gut micsrobiome.

Studies show that traditional Chinese medicine (TCM), such as Liujunanwei (LJAW) decoction, can play important roles in alleviating side effects of chemotherapy. The purpose of this study was to understand how LJAW can counter chemotherapy-induced emesis via alteration of gut microbiota. We evaluated the effect of LJAW on cisplatin (DDP)-induced nausea and vomiting using a rat-pica model. Rats react to emetic-producing stimuli with increased kaolin consumption, a phenomenon called pica. The rats were injected with cisplatin and then randomly assigned to the control (DDP), Ondansetron or LJAW. The intake of kaolin and chow diet as well as body weights were recorded every 24 hours. Fecal samples were collected prior to, after three and seven days of treatment. The expression of proteins was measured by western blot. The concentration of cytokines and serotonin was evaluated using ELISA assay kits. Kaolin consumption in rats induced by cisplatin was reduced by 16.5%, 22.5%, and 30.1% in the LJAW group compared to the DDP group at 24 hours, 48 hours and 72 hours, respectively (p>0.05). LJAW significantly increased the food intake of the rats (13.94 ± 4.73 g) during the first 24 hours as opposed to the DDP (9.23 ± 3.77 g) (p<0.05). 16S rRNA gene sequencing showed the abundance of Bacteroidetes increased in cisplatin treated rats. In addition, cisplatin injection caused an enrichment of Escherichia-Shigella and Enterococcus at the genus level. While, enrichment of Blautia and Lactobacillus was presented in LJAW treated rats. Serotonin decreased in LJAW treated intestine and medulla oblongata tissues. Further, the protein expression of tryptophan hydroxylase 1 (TPH1) a rate limiting enzyme of serotonin was inhibited in LJAW treated rat’s jejunum compared with cisplatin only treated rats. In addition, LJAW downregulated chemotherapy induced elevated inflammation. The results of this study indicated that LJAW is capable of decreasing cisplatin-induced kaolin intake in rat-nausea model (pica), which might be mediated through gut microbiome-induced anti-inflammation and anti-serotonin synthesis functions.

Olanzapine Administration Reduces Chemotherapy-Induced Nausea Behavior in Rats

Nausea and vomiting are consistently identified among the most distressing side effects of chemotherapy. In recent years, Olanzapine (OLZ) treatment was added to anti-emetic guidelines as a treatment for chemotherapy-induced nausea and vomiting (CINV), despite little available data supporting a mechanism behind the positive benefits of the drug. Here, we examine whether OLZ reduces cisplatin chemotherapy-induced side effects on food intake and pica behavior in rats (i.e., kaolin intake, a proxy for nausea/emesis). Behavioral experiments tested whether systemic or hindbrain administration of OLZ ameliorated cisplatin-induced pica, anorexia, and body weight loss in rats. We also tested whether systemic OLZ reduces cisplatin-induced neuronal activation in the dorsal vagal complex (DVC), a hindbrain region controlling emesis. Lastly, given their role in regulating feeding and emesis, circulating ghrelin levels and central mRNA expression levels of serotonin (HT) receptor subunits, including 5-HT2C, were measured in brain regions that regulate CINV and energy balance in an exploratory analysis to investigate potential mediators of OLZ action. Our results show that both systemic and hindbrain administration of OLZ attenuated cisplatin-induced kaolin intake and body weight loss, but not anorexia. Systemic OLZ decreased cisplatin-induced c-Fos immunofluorescence in the DVC and prevented cisplatin-induced reductions in circulating ghrelin levels. IP OLZ also blocked cisplatin-induced increases in Htr2c expression in DVC and hypothalamic micropunches. These data suggest hindbrain exposure to OLZ is sufficient to induce reductions in cisplatin-induced pica and that central serotonergic signaling, via 5-HT2C, and changes in circulating ghrelin may be potential mediators of olanzapine anti-emetic action.

Gingerol inhibits cisplatin-induced acute and delayed emesis in rats and minks by regulating the central and peripheral 5-HT, SP, and DA systems

Gingerol, a biologically active component in ginger, has shown antiemetic properties. Our study aimed to explore the underlying mechanisms of gingerol on protecting rats and minks from chemotherapy-induced nausea and vomiting. The preventive impact of gingerol was evaluated in the pica model of rats and the vomiting model of minks induced by cisplatin at every 6 h continuously for a duration of 72 h. Animals were arbitrarily separated into blank control group, simple gingerol control group, cisplatin control group, cisplatin + metoclopramide group, cisplatin + three different doses gingerol group (low-dose; middle-dose; high-dose). The area postrema as well as ileum damage were assessed using H&E stain. The levels of 5-TH, 5-HT3 receptor, TPH, SERT, SP, NK1 receptor, PPT, NEP, DA, D2R, TH, and DAT were determined using immunohistochemistry or qRT-PCR in rats and minks. All indicators were measured in the area postrema along with ileum. The kaolin intake by rats and the incidence of CINV of minks were significantly decreased after pretreatment with gingerol in a dosage-dependent way for the duration of 0–24-h and 24–72-h. Gingerol markedly decreased the levels of 5-TH, 5-HT3 receptor, TPH, SP, NK1 receptor, PPT, DA, D2R, TH, alleviated area postrema as well as ileum damage, and increased the accumulation of SERT, NEP, DAT in the area postrema along with ileum of rats and minks. Gingerol alleviates cisplatin-induced kaolin intake of rats and emesis of minks possibly by regulating central and peripheral 5-HT system, SP system and DA system.Graphic abstract

The effects of different tropisetron administration routes and dosages on cisplatin-induced kaolin intake in rats

Objective To compare the effects of different administration routes and dosages of tropisetron on cisplatin-induced kaolin intake in rats.Methods Ninety-six healthy adult male Wistar SPF rats were randomly divided into 8 groups(n =12 each):intrathecal (IT) control group (group TC) and 3 tropisetron groups receiving IT tropisetron 10,20 and 30 μg,the volume of each group was 30 μl (group T10,T20,T30),intravenous(Ⅳ) control group (group IC) and 3 tropisetron groups receiving Ⅳ tropisetron 0.3,0.5 and 0.7 mg/kg respectively (group I0.3,I0.5,I0.7).In group TC and IC,normal saline 30 μl and 0.5 ml were injected IT and Ⅳ,respectively.All rats received cisplatin 3mg/kg by intraperitoneal injection at the time point of thirty minutes after administration,each rat weight,the daily food and kaolin intakes were detected at the time point of 48 hours after cisplatin administration.Results Compared with group Tc,each rat weight loss,the kaolin intakes were significantly decreased (P ＜ 0.05),and food intake dose was significantly increased in group T20 (P ＜ 0.05).Compared with group IC,each rat weight loss,the kaolin intakes were significantly decreased (P ＜ 0.05),and food intake dose was significantly increased in group I0.5 and I0.7 (P ＜0.05).There was no significant difference between group I0.5,I0.7 and group T20.Conclusions The kaolin intakes and the rat weight loss can be decreased by IT tropisetron,and the food take dose was increased meanwhile,and IT tropisetron 20 μg has equivalent efficacy to IV tropisetron 0.5 or 0.7 mg/kg.IT could be the new administration route of tropisetron. Key words: Indoles/administration & dosage; Pica/etiology; Cisplatin/adverse effects

Pemirolast reduces cisplatin-induced kaolin intake in rats

Emesis is the most feared side effect in patients who are undergoing cancer chemotherapy. In particular, cisplatin causes severe acute and delayed emesis. Although early vomiting is well controlled by 5-hydroxytryptamine 3 (5-HT 3) receptor antagonists, delayed-phase vomiting is not sufficiently controlled. Substance P is thought to be involved in the development of emesis, and tachykinin NK 1 receptor antagonists can inhibit delayed vomiting. We previously have reported that substance P is involved in the paclitaxel-induced hypersensitivity reaction in rats, and anti-allergic agent pemirolast reduces these reactions via inhibition of substance P release. In the present study, we investigated the effect of pemirolast on cisplatin-induced kaolin intake, which is an index of nausea/vomiting in the rat. Cisplatin (5 mg/kg, i.p.) induced kaolin intake and reduced normal feed intake from days 1 to 5 after injection. Cisplatin-induced kaolin intake was significantly reduced by co-administration of ondansetron (2 mg/kg, i.p.), a 5-HT 3 receptor antagonist, and dexamethasone (2 mg/kg, i.p.) from days 1 to 5. Similarly, pemirolast (10 mg/kg, p.o.) and the tachykinin NK 1 receptor antagonist aprepitant (10 and 30 mg/kg, p.o.) significantly reduced cisplatin-induced kaolin intake on days 3 and 4. Moreover, pemirolast at the same dose significantly reversed the cisplatin-induced increase in the cerebrospinal fluid level of substance P in rats. These results suggest that substance P is involved in cisplatin-induced kaolin intake in rats, and pemirolast reduces kaolin intake by inhibition of substance P release.

Effects of Korean ginseng root extract on cisplatin-induced emesis in a rat-pica model

In the present study, we investigate the effect of Korean ginseng root extract (KG) on cisplatin-induced pica in a rat model. Rats were treated with KG before (25, 50, and 100mg/kg) or after (12.5, 25, and 50mg/kg) a single intraperitoneal injection of cisplatin (7 and 6mg/kg, respectively). We examined intake of kaolin and normal food as an indicator of the emetic stimulus every 24h for 120h. Changes in body weight, haematology and histopathology were additionally assessed. Pre-treatment with KG (25 and 50mg/kg) significantly attenuated cisplatin-induced kaolin intake (24, 48, and 72h) and markedly improved intake of normal food by rats at 48, 72, 96, and 120h. Cisplatin-induced kaolin intake was markedly decreased upon post-treatment of rats with KG (12.5, 25, and 50mg/kg) at 24h. Notably, post-treatment with the lowest KG dose resulted in a significant anti-pica effect and improved food intake until 72h. The magnitude of body weight reduction was significantly diminished in rats pre-treated/post-treated with 25, 50, and 12.5mg/kg KG. The anti-pica effects of KG were further confirmed with haematological and histopathological findings. Our findings collectively indicate that KG improves the resistance of rats against emesis.

S2077 Gastric Electrical Response to Different Stimulation Parameters via Intraoperative Egg Recordings

Background and Aims: Acupuncture or electroacupuncture (EA) has been applied for treating chemotherapy-induced emesis with limited success. Two major problems with EA include infrequent application of EA and suboptimal stimulation parameters. The aims of this study were to investigate the feasibility of EA using chronically implanted electrodes and the effects of EA with different parameters on cisplatin-induced emesis in rats assessed by pica (intake of kaolin) that has been validated as a surrogate of emesis in rats. Materials and Methods: Under anesthesia, 19 SD rats were chronically implanted with a pair of electrodes at bilateral acupoint PC6 as follows: A 3mm tip of the exposed wire (serving as an electrode) was inserted into the acupoint and the connecting wire was firstly fixed in the muscle layer around the acupoint, then tunneled subcutaneously to the back of the neck and finally exited and protected for EA. After recovery and appropriate acclimation, the rats were treated using a 3×3 Latin Square cross-over design in which each rat received a sequence of 3 treatments in one of 3 assigned orders. The treatments included the following: EA1: 20Hz, 0.6ms, 2mA and continuous stimulation; EA2: 10Hz, 1.2ms, 2mA and continuous stimulation; Control: no stimulation. During each treatment, cisplatin 6mg/kg was injected intraperitoneally at 3PM during the first day and the rats received with one of the three treatments while staying at a rat restrainer for 3 hrs from 6pm-9m daily for 2 days. During the other periods, the rats were housed in their individual cages. There was an interval of 2 weeks between the two consecutive treatments. Results: 1) The implanted electrodes remained secured at the acupoints without infections. 2) Cisplatin induced substantial kaolin intake as well as reduced food intake and body weight; Treatment with EA1 significantly reduced kaolin intake on the first and second day after cisplatin in comparison with the control (first day, EA1 vs. Control, 1.0±0.2 vs.1.9±0.3g, p=0.017; second day, 0.4±0.2 vs.1.1±0.3g, p= 0.010); 3) Treatment with EA2 had no effects on kaolin intake after Cisplatin. Conclusions: Electrical stimulation via chronically implanted electrodes at acupoints is feasible. That is, EA may be performed chronically and continuously using implantable electrodes and pulse generator. EA at PC6 with appropriate parameters is able to reduce Cisplatin-induced kaolin intake in rats, suggesting an ameliorating effect on chemotherapy-induced emesis. The significant difference in the performance of EA with different parameter sets demonstrates the importance of parameter optimization in the application of EA.

S2076 A Novel Method of Electrical Stimulation via Electrodes Chronically Implanted at Acupoints and Its Effect on Cisplatin-Induced Emesis in Rats Assessed by Pica

Background and Aims: Acupuncture or electroacupuncture (EA) has been applied for treating chemotherapy-induced emesis with limited success. Two major problems with EA include infrequent application of EA and suboptimal stimulation parameters. The aims of this study were to investigate the feasibility of EA using chronically implanted electrodes and the effects of EA with different parameters on cisplatin-induced emesis in rats assessed by pica (intake of kaolin) that has been validated as a surrogate of emesis in rats. Materials and Methods: Under anesthesia, 19 SD rats were chronically implanted with a pair of electrodes at bilateral acupoint PC6 as follows: A 3mm tip of the exposed wire (serving as an electrode) was inserted into the acupoint and the connecting wire was firstly fixed in the muscle layer around the acupoint, then tunneled subcutaneously to the back of the neck and finally exited and protected for EA. After recovery and appropriate acclimation, the rats were treated using a 3×3 Latin Square cross-over design in which each rat received a sequence of 3 treatments in one of 3 assigned orders. The treatments included the following: EA1: 20Hz, 0.6ms, 2mA and continuous stimulation; EA2: 10Hz, 1.2ms, 2mA and continuous stimulation; Control: no stimulation. During each treatment, cisplatin 6mg/kg was injected intraperitoneally at 3PM during the first day and the rats received with one of the three treatments while staying at a rat restrainer for 3 hrs from 6pm-9m daily for 2 days. During the other periods, the rats were housed in their individual cages. There was an interval of 2 weeks between the two consecutive treatments. Results: 1) The implanted electrodes remained secured at the acupoints without infections. 2) Cisplatin induced substantial kaolin intake as well as reduced food intake and body weight; Treatment with EA1 significantly reduced kaolin intake on the first and second day after cisplatin in comparison with the control (first day, EA1 vs. Control, 1.0±0.2 vs.1.9±0.3g, p=0.017; second day, 0.4±0.2 vs.1.1±0.3g, p= 0.010); 3) Treatment with EA2 had no effects on kaolin intake after Cisplatin. Conclusions: Electrical stimulation via chronically implanted electrodes at acupoints is feasible. That is, EA may be performed chronically and continuously using implantable electrodes and pulse generator. EA at PC6 with appropriate parameters is able to reduce Cisplatin-induced kaolin intake in rats, suggesting an ameliorating effect on chemotherapy-induced emesis. The significant difference in the performance of EA with different parameter sets demonstrates the importance of parameter optimization in the application of EA.

Chemotherapy-induced kaolin intake is increased by lesion of the lateral parabrachial nucleus of the rat

Anticancer agents, such as cisplatin, stimulate nausea, vomiting, and behaviors indicative of malaise. Rats and mice do not possess a vomiting response, and, therefore, in these species, the ingestion of kaolin clay (a pica response) has been used as an index of malaise. In the rat, cisplatin-induced kaolin intake is inhibited by antiemetic treatments. In addition, cisplatin activates vagal afferent fibers in the gut, and kaolin intake induced by cisplatin is largely dependent on an intact vagus. Nevertheless, little is known about the brain pathways controlling pica. We investigated the role of the lateral parabrachial nucleus (lPBN), a major visceral afferent link between the hindbrain and forebrain, in cisplatin-induced c-Fos expression and pica. Injection of cisplatin (6 mg/kg ip) produced c-Fos expression in the ventrolateral (external) lPBN, a region receiving viscerosensory input. In rats with bilateral ibotenic acid lPBN lesions, cisplatin treatment substantially increased kaolin intake compared with controls ( approximately 30 g vs. approximately 5 g, respectively, over 24 h). Food intake was reduced by cisplatin treatment and by apomorphine, an emetic agent that acts centrally. Unlike cisplatin, however, apomorphine stimulated kaolin intake to a similar degree in both the lesioned and control rats, suggesting that lPBN damage neither produces nonspecific effects nor enhances malaise in general. These data suggest that lPBN-lesioned animals not only demonstrate pica after cisplatin treatment, but, in fact, show an exaggerated response that is greatly in excess of any treatment known to produce kaolin intake in rats.

Brain Fos expression induced by the chemotherapy agent cisplatin in the rat is partially dependent on an intact abdominal vagus

Anticancer agents such as cisplatin stimulate nausea, vomiting, and behaviors indicative of malaise. Rats and mice, and probably all rodents, do not possess a vomiting response, and their ingestion of kaolin clay (a pica response) has been used as an index of malaise. Similar to the action of cisplatin on emesis in vomiting species, in the rat cisplatin activates vagal afferent fibers, and cisplatin-induced kaolin intake is largely dependent on an intact abdominal vagus. Cisplatin also stimulates Fos expression in the rat brain in areas known to play a role in emesis in other species, but it is not known whether vagal input is required for this CNS activation. In the present study, rats were given abdominal vagotomy or sham operation to test the role of an intact vagus on cisplatin-induced Fos expression 6 h after injection with saline or cisplatin (6 mg/kg, ip). Cisplatin treatment produced Fos expression in the area postrema and multiple levels of the nucleus of the solitary tract (NTS) of sham-operated rats. Vagotomy reduced cisplatin-induced Fos expression in the caudal and middle levels of the NTS and central amygdala. Furthermore, cisplatin did not significantly alter Fos expression in the spinal cord (T8–T10) before or after vagotomy. These results suggest that a defined portion of cisplatin-induced Fos expression is dependent on vagal input, with a majority of this response determined by either direct action of cisplatin or humoral factors on the CNS.

American ginseng berry extract and ginsenoside Re attenuate cisplatin-induced kaolin intake in rats

Cisplatin, a chemotherapeutic agent, causes significant nausea and vomiting. It is postulated that cisplatin-induced oxidant stress may be responsible for these symptoms. We tested whether pretreatment with American ginseng berry extract (AGBE), an herb with potent antioxidant capacity, and one of its active antioxidant constituents, ginsenoside Re, could counter cisplatin-induced emesis using a rat pica model. In rats, exposure to emetic stimuli such as cisplatin causes significant kaolin intake, a phenomenon called pica. We therefore measured cisplatin-induced kaolin intake as an indicator of the emetic response. Rats were pretreated with vehicle, AGBE (dose range 50-150 mg/kg, IP) or ginsenoside Re (2 and 5 mg/kg, IP). Rats were treated with cisplatin (3 mg/kg, IP) 30 min later. Kaolin intake, food intake, and body weight were measured every 24 h for 120 h. Additionally, the free radical scavenging activity of AGBE was measured in vitro using ESR spectroscopy. A significant dose-response relationship was observed between increasing doses of pretreatment with AGBE and reduction in cisplatin-induced pica. Kaolin intake was maximally attenuated by AGBE at a dose of 100 mg/kg. Food intake also improved significantly at this dose (P<0.05). Pretreatment with ginsenoside Re (5 mg/kg) also decreased kaolin intake (P<0.05). In vitro studies demonstrated a concentration-response relationship between AGBE and its ability to scavenge superoxide and hydroxyl radicals. Pretreatment with AGBE and its major constituent, Re, attenuated cisplatin-induced pica, and demonstrated potential for the treatment of chemotherapy-induced nausea and vomiting. Significant recovery of food intake further strengthens the conclusion that AGBE may exert an antinausea/antiemetic effect.

Effects of Ganoderma lucidum Extract on Chemotherapy-Induced Nausea and Vomiting in a Rat Model

Chemotherapy is highly cytotoxic, causing a number of severe adverse effects such as nausea and vomiting. Herbal medicines, which can often be used on a daily basis for prolonged treatment, may be clinically beneficial. Ganoderma lucidum or Lingzhi mushroom has been recognized as a remedy in treating a number of medical conditions, including balancing immunity and decreasing drug-induced side effects. It has been shown that rats react to emetic stimuli, like the chemotherapy agent cisplatin, by increased consumption of kaolin, known as pica; and this rat model has been utilized to evaluate novel anti-emetic compounds. In this study, we evaluated the effects of a G. lucidum extract (SunRecome, the most commonly used Lingzhi mushroom extract in China) in attenuating cisplatin-induced nausea and vomiting in the rat pica model. We observed that intraperitoneal cisplatin injection caused a significant increase in kaolin intake at 24, 48, 72 and 96 hours, reflecting cisplatin's nausea and vomiting action. This cisplatin-induced kaolin intake dose-dependently decreased after 1, 3 and 10 mg/kg G. lucidum extract injection (p < 0.01). In addition, there was a significant reduction of food intake after cisplatin. The cisplatin-induced food intake reduction improved significantly after G. lucidum extract administrations in a dose-related manner (p < 0.01), suggesting a supportive effect of the extract on general body condition. Future controlled clinical trials are needed to evaluate the safety and effectiveness of this herbal medication.

Scutellaria baicalensis extract decreases cisplatin-induced pica in rats.

Nausea/vomiting are significant side effects associated with the use of chemotherapy in cancer patients. Treatment of nausea/vomiting caused by cisplatin, a potent chemotherapeutic agent and one of the most emetogenic stimuli, requires a combination of different antiemetic drugs. In this study, we investigated the effects of Scutellaria baicalensis, an antioxidant herbal medicine, on cisplatin-induced nausea using a rat model. Rats react to emetic/nausea-producing stimuli, such as cisplatin, with altered feeding habits, manifested by pica or increased consumption of kaolin (a type of clay). We measured pica in rats to quantify cisplatin-induced nausea, and to evaluate the antinausea effect of pretreatment with S. baicalensis extract (SbE) given intraperitoneally. Cisplatin at 3 mg/kg induced significant pica accompanied by reduced food intake, suggesting the presence of nausea. Hence, this cisplatin dose was selected for testing the antinausea activity of SbE. Cisplatin-induced pica decreased significantly when animals were pretreated with SbE at doses of 1 mg/kg and 3 mg/kg ( P<0.01). At a higher SbE dose (10 mg/kg), kaolin consumption increased, rather than further decreased, and was significantly different from that in the groups treated with low SbE doses. SbE pretreatment decreased cisplatin-induced kaolin intake in the rat model of simulated nausea, suggesting that SbE and its active constituent(s) may play a therapeutic role in chemotherapy-induced emesis. Absence of therapeutic effect at the highest tested SbE dose could have been a result of prooxidant activity often associated with excess antioxidant concentration.

Effects of HSP-117, a Novel Tachykinin NK-Receptor Antagonist, on Cisplatin-Induced Pica as a New Evaluation of Delayed Emesis in Rats

The effects of a novel tachykinin NK1-receptor antagonist HSP-117 [(2S,3S)-3-[(5-isopropyl-2,3-dihydrobenzofuran-7-yl)methyl]amino-2-phenylpiperidine dihydrochloride] on cisplatin-induced pica, i.e., the eating of nonnutritive substances such as kaolin were examined in rats. HSP-117 inhibited kaolin intake in a dose-dependent manner for 2 days. The 5-HT3-receptor antagonist ondansetron inhibited only on the first day, but not on the second day. These results indicate that the cisplatin-induced kaolin intake on the first day is related to both 5-HT3- and NK1 receptors, while only the NK1 receptor is involved on the second day. Thus, cisplatin-induced continuous pica in rats represents a useful model of not only acute but also delayed emesis.

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 D 2 receptors in the chemoreceptor trigger zone, and 2) the stomach, partly via 5-HT 3 receptors in the visceral afferents in the stomach wall. The present findings support the conclusion that pica i 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.