The gene expression of the hypothalamic feeding-regulating peptides in cisplatin-induced anorexic rats

Yoshimura, Mitsuhiro; Matsuura, Takanori; Ohkubo, Jun‐ichi; Ohno, Motoko; Maruyama, Takashi; Ishikura, Toru; Hashimoto, Hirofumi; Kakuma, Tatsuyuki; Yoshimatsu, Hironobu; Terawaki, Kiyoshi; Uezono, Yasuhito; Ueta, Yoichi

doi:10.1016/j.peptides.2013.04.019

Cited by 30 publications

(29 citation statements)

References 20 publications

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“…We previously described changes in the gene expression of the hypothalamic feeding-regulating neuropeptides in cisplatin-treated rats [13]. In this study, the gene expression of CRH in the PVN and the gene expression of NPY in the ARC were significantly decreased, while the gene expressions of POMC and CART in the ARC were markedly increased in cisplatin-treated rats compared to saline-treated rats.…”

Section: Cisplatin-induced Anorexiamentioning

confidence: 47%

“…The typical models of physiological anorexia are dehydrationinduced anorexia and stress-induced anorexia [9][10][11][12]. On the other hand, the typical models of pathophysiological anorexia are drug-induced anorexia, lipopolysaccharides (LPS)-induced anorexia, anti-cancer drug-induced anorexia as a side effect and cancer-induced cachexia-anorexia [13][14][15]. From the point of view of hypothalamic neuropeptides, distinct patterns of the orexigenic or anorexigenic neuropeptides are seen among these anorexia models.…”

Section: Introductionmentioning

confidence: 99%

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Anorexia in human and experimental animal models: physiological aspects related to neuropeptides

Yoshimura

Uezono²,

Ueta

2015

J Physiol Sci

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Anorexia, a loss of appetite for food, can be caused by various physiological and pathophysiological conditions. In this review, firstly, clinical aspects of anorexia nervosa are summarized in brief. Secondly, hypothalamic neuropeptides responsible for feeding regulation in each hypothalamic nucleus are discussed. Finally, three different types of anorexigenic animal models; dehydration-induced anorexia, cisplatin-induced anorexia and cancer anorexia-cachexia, are introduced. In conclusion, hypothalamic neuropeptides may give us novel insight to understand and find effective therapeutics strategy essential for various kinds of anorexia.

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Section: Cisplatin-induced Anorexiamentioning

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Anorexia in human and experimental animal models: physiological aspects related to neuropeptides

Yoshimura

Uezono²,

Ueta

2015

J Physiol Sci

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“…Thus, rikkunshito may ameliorate anorexia by activating GHSR-NPY/AgRP orexigenic signaling in the ARC and PVN. In fact, our previous study demonstrated that rikkunshito ameliorated cisplatin-induced anorexia in rats and reversed the cisplatin-induced decrease in hypothalamic orexigenic peptide mRNA levels (NPY in ARC) and increase in anorexigenic peptide mRNA levels (POMC and CART in the ARC) (65). Because anorexia induced by cancer cachexia and cisplatin may involve different mechanisms, further study is required to clarify the mechanisms by which rikkunshito ameliorates cancer cachexia-induced anorexia.…”

Section: Discussionmentioning

confidence: 97%

“…Interestingly, our previous study using a cisplatin-induced cachexia rat model yielded contrasting results to those of the 85As2 model, although both models exhibited decreased food intake. In the cisplatin-induced cachexia model, hypothalamic orexigenic peptide mRNA levels decreased and anorexigenic peptide mRNA levels increased (65). Cisplatin has been shown to reduce the secretion of ghrelin that activates NPY neurons, whereas it inhibits POMC and CART expression in the ARC (34,57).…”

Section: Discussionmentioning

confidence: 99%

New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line

Terawaki

Sawada²,

Kashiwase

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC. cachexia; leukemia inhibitory factor; rikkunshito; stomach cancer model; anorexia CANCER CACHEXIA, A MULTIFACTORIAL SYNDROME characterized by anorexia and the loss of body weight, adipose tissue, and skeletal muscle, is observed in 80% of advanced cancer patients and accounts for at least 20% of cancer-related deaths (20,35,42). This syndrome causes not only poor quality of life (QOL) but also poor responses to chemotherapy, highlighting the need for improved cancer cachexia treatments. Weight loss, the most prominent clinical feature of cachexia, is observed in 30 -80% of cancer patients, depending on tumor type. For example, weight loss occurs at a very high frequency (83%) in stomach and pancreatic cancer patients but is less prominent in patients with breast cancer, acute nonlymphocytic leukemia, and sarcomas (35). Although cachexia strongly impacts the success of therapeutic treatments, the mechanisms underlying this syndrome are not fully understood. Stomach cancer patients in particular have the highest incidence of cachexia; however, few experimental models for the study of stomach cancer cachexia have been established (4,14,66).A useful cachexia model must meet three of the following five diagnostic criteria in addition to weight loss: anorexia, decreased muscle strength, fatigue, low fat-free mass (FFM) index, and abnormal biochemistry (anemia, in...

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“…According to the appetite modulation model, hypothalamus neurons can divided into two distinct neuronal populations: orexigenic neuropeptides (an appetite stimulant), including neuropeptide Y (NPY) and agouti‐related peptide (AgRP), and anorexigenic neuropeptides, including proopiomelanocortin (POMC) and cocaine‐ and amphetamine‐regulated transcript (CART) . Cisplatin alters the expression of these neurons and thereby leads to anorexia …”

Section: Introductionmentioning

confidence: 99%

D‐methionine improves cisplatin‐induced anorexia and dyspepsia syndrome by attenuating intestinal tryptophan hydroxylase 1 activity and increasing plasma leptin concentration

Wong

Lin

Liu

et al. 2020

Neurogastroenterology Motil

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Background:Cisplatin is a widely used antineoplastic drug. However, cisplatin-induced dyspepsia syndromes, including delayed gastric emptying, gastric distension, early satiety, nausea, and vomiting, often force patients to take doses lower than those prescribed or even refuse treatment. D-methionine has an appetite-enhancing effect and alleviates weight loss during cisplatin treatment. Methods:This work established a model of anorexia and dyspepsia symptoms with intraperitoneal injection of cisplatin (5 mg/kg) once a week for three cycles.Presupplementation with or without D-methionine (300 mg/kg) was performed.Orexigenic and anorexigenic hormones (ghrelin, leptin, and glucagon-like peptide-1), tryptophan hydroxylase 1 (TPH1), 5-hydroxytryptamine receptors (5-HT 2C and 5-HT 3 ), and hypothalamic feeding-related peptides were measured by immunohistochemistry staining, enzyme-linked immunosorbent assay, and real-time PCR assay.Key results: Cisplatin administration caused marked decrease in appetite and body weight, promoted adipose and fat tissue atrophy, and delayed gastric emptying and gastric distension, and D-methionine preadministration prior to cisplatin administration significantly ameliorated these side effects. Besides, cisplatin induced an evident increase in serum ghrelin level, TPH1 activity, and 5-HT 3 receptor expression in the intestine and decreased plasma leptin levels and gastric ghrelin mRNA gene expression levels. D-methionine supplementation recovered these changes. The expression of orexigenic neuropeptide Y/ agouti-related peptide and anorexigenic cocaine-and amphetamine-regulated transcript proopiomelanocortin neurons were altered by D-methionine supplementation in cisplatininduced anorexia rats. Conclusions and inferences: D-methionine supplementation prevents cisplatin-in-duced anorexia and dyspepsia syndrome possibly by attenuating intestinal tryptophan hydroxylase 1 activity and increasing plasma leptin concentration. Therefore, D-methionine can be used as an adjuvant therapy for treating cisplatin-induced adverse effects.

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The gene expression of the hypothalamic feeding-regulating peptides in cisplatin-induced anorexic rats

Cited by 30 publications

References 20 publications

Anorexia in human and experimental animal models: physiological aspects related to neuropeptides

Anorexia in human and experimental animal models: physiological aspects related to neuropeptides

New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line

D‐methionine improves cisplatin‐induced anorexia and dyspepsia syndrome by attenuating intestinal tryptophan hydroxylase 1 activity and increasing plasma leptin concentration

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