Psychiatric Adverse Events of Acetylcholinesterase Inhibitors in Alzheimer's Disease and Parkinson's Dementia: Systematic Review and Meta-Analysis.

BACKGROUND: The acetylcholinesterase inhibitors (AChEIs) donepezil, galantamine, and rivastigmine are commonly used in the management of various forms of dementia. OBJECTIVES: While these drugs are known to induce classic cholinergic adverse events such as diarrhea, their potential to cause psychiatric adverse events has yet to be thoroughly examined. METHODS: We sought to determine the risk of psychiatric adverse events associated with the use of AChEIs through a systematic review and meta-analysis of double-blind randomized controlled trials involving patients with Alzheimer's dementia and Parkinson's dementia. RESULTS: A total of 48 trials encompassing 22,845 patients were included in our analysis. Anorexia was the most commonly reported psychiatric adverse event, followed by agitation, insomnia, and depression. Individuals exposed to AChEIs had a greater risk of experiencing appetite disorders, insomnia, or depression compared with those who received placebo (anorexia: odds ratio [OR] 2.93, 95% confidence interval [CI] 2.29-3.75; p < 0.00001; decreased appetite: OR 1.93, 95% CI 1.33-2.82; p = 0.0006; insomnia: OR 1.55, 95% CI 1.25-1.93; p < 0.0001; and depression: OR 1.59, 95% CI 1.23-2.06, p = 0.0004). Appetite disorders were also more frequent with high-dose versus low-dose therapy. A subgroup analysis revealed that the risk of insomnia was higher for donepezil than for galantamine. CONCLUSIONS: Our findings suggest that AChEI therapy may negatively impact psychological health, and careful monitoring of new psychiatric symptoms is warranted. Lowering the dose may resolve some psychiatric adverse events, as may switching to galantamine in the case of insomnia. CLINICAL TRIAL REGISTRATION: The study was pre-registered on PROSPERO (CRD42021258376).

Effects of Rikkunshi-To, a Japanese kampo medicine, on donepezil-induced gastrointestinal side effects in mice.

Donepezil, an acetylcholinesterase inhibitor, is associated with gastrointestinal symptoms, such as nausea, vomiting, and anorexia, which may affect adherence to continuous therapy. Since Rikkunshi-To, a Japanese herbal medicine, activates the ghrelin signaling pathway and promotes gastrointestinal function, it is administered to prevent gastrointestinal symptoms. We herein investigated whether donepezil-induced gastrointestinal side effects in mice are ameliorated by Rikkunshi-To and if its therapeutic efficacy is mediated by ghrelin. Since pica behavior, the ingestion of kaolin, correlates with nausea and vomiting in humans, donepezil was intraperitoneally administered with or without Rikkunshi-To daily to mice, and food and kaolin intakes were monitored. The effects of donepezil on intestinal motility and a ghrelin receptor antagonist on donepezil-induced pica behavior, anorexia, and changes in intestinal motility were examined in mice treated with Rikkunshi-To. Pica behavior and anorexia were significantly induced by donepezil and significantly inhibited by Rikkunshi-To. Intestinal motility was significantly suppressed by donepezil and promoted by Rikkunshi-To. Furthermore, the therapeutic effects of Rikkunshi-To were antagonized by the ghrelin receptor antagonist. The present results support the therapeutic efficacy of Rikkunshi-To against donepezil-induced gastrointestinal side effects.

Role of Kampo Medicine in Modern Cancer Therapy: Towards Completion of Standard Treatment.

Kampo Medicine is a traditional Japanese medicine and is well integrated with modern medicine. Anticancer agents are highly developed, and evidence regarding standard treatment has accumulated. Kampo Medicine helps support patients with cancer who lack vital energy and feel cold. Cancer chemotherapy is associated with adverse reactions that are refractory to modern therapy, such as anorexia, general malaise/fatigue, and peripheral neuropathy. Recently, evidence of the effectiveness of Kampo Medicines for these symptoms has been reported in randomized controlled trials (RCTs). The Japan Society for Oriental Medicine celebrated the first 20 years of its evidence-based medicine (EBM) committee in June 2021. The activities of this committee include publication of the Evidence Reports of Kampo Treatment, which contains RCTs and meta-analyses, including RCTs on cancer supportive care. Evidence is accumulating for hangeshashinto for mucositis, rikkunshito for anorexia, goshajinkigan and ninjin'yoeito for peripheral neuropathy, hochuekkito for general malaise/fatigue, and shakuyakukanzoto for myalgia/arthralgia. However, additional evidence and further clinical trials are needed. Supportive care with Kampo Medicine increases the likelihood of completing standard treatment for cancer.

The hyperthermic effect of central cholecystokinin is mediated by the cyclooxygenase-2 pathway.

Cholecystokinin (CCK) increases core body temperature via CCK2 receptors when administered intracerebroventricularly (icv). The mechanisms of CCK-induced hyperthermia are unknown, and it is also unknown whether CCK contributes to the fever response to systemic inflammation. We studied the interaction between central CCK signaling and the cyclooxygenase (COX) pathway. Body temperature was measured in adult male Wistar rats pretreated with intraperitoneal infusion of the nonselective COX enzyme inhibitor metamizol (120 mg/kg) or a selective COX-2 inhibitor, meloxicam, or etoricoxib (10 mg/kg for both) and, 30 min later, treated with intracerebroventricular CCK (1.7 µg/kg). In separate experiments, CCK-induced neuronal activation (with and without COX inhibition) was studied in thermoregulation- and feeding-related nuclei with c-Fos immunohistochemistry. CCK increased body temperature by ∼0.4°C from 10 min postinfusion, which was attenuated by metamizol. CCK reduced the number of c-Fos-positive cells in the median preoptic area (by ∼70%) but increased it in the dorsal hypothalamic area and in the rostral raphe pallidus (by ∼50% in both); all these changes were completely blocked with metamizol. In contrast, CCK-induced satiety and neuronal activation in the ventromedial hypothalamus were not influenced by metamizol. CCK-induced hyperthermia was also completely blocked with both selective COX-2 inhibitors studied. Finally, the CCK2 receptor antagonist YM022 (10 µg/kg icv) attenuated the late phases of fever induced by bacterial lipopolysaccharide (10 µg/kg; intravenously). We conclude that centrally administered CCK causes hyperthermia through changes in the activity of "classical" thermoeffector pathways and that the activation of COX-2 is required for the development of this response.NEW & NOTEWORTHY An association between central cholecystokinin signaling and the cyclooxygenase-prostaglandin E pathway has been proposed but remained poorly understood. We show that the hyperthermic response to the central administration of cholecystokinin alters the neuronal activity within efferent thermoeffector pathways and that these effects are fully blocked by the inhibition of cyclooxygenase. We also show that the activation of cyclooxygenase-2 is required for the hyperthermic effect of cholecystokinin and that cholecystokinin is a modulator of endotoxin-induced fever.

Liujunzi Decoction ameliorated cisplatin-induced anorexia by inhibiting the JAK-STAT signaling pathway and coordinating anorexigenic and orexigenic neuropeptides in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese formula, Liujunzi Decoction (LJZD) originated from the Yi Xue Zheng Zhuan, and has a promising effect in treating chemotherapy-induced anorexia (CIA). AIM OF THE STUDY: The present study aims to investigate whether LJZD acts on interleukin-6 (IL-6)/leptin mediated janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway that regulates hypothalamus anorexigenic and orexigenic peptides to ameliorate CIA, and also elucidates the potential mechanism by metabolomic analysis. MATERIALS AND METHODS: Network pharmacology analyses were conducted to screen out potential targets and pathways. The CIA rat model was established via an intraperitoneal injection of cisplatin. The histological changes of gastric antrum, liver and ileum were observed by HE staining. The serum levels of leptin, ghrelin, IL-6 and growth differentiation factor 15 (GDF15) were measured by ELISA. The JAK1/2 and STAT levels in gastric antrum and hypothalamus were detected by Western blot. The transcriptions of gastric antrum and hypothalamus IL-6R mRNA, and hypothalamus cocaine- and amphetamine-regulated transcript (CART), pro-opiomelanocortin (POMC), thyrotropin-releasing hormone (TRH), upregulated orexigenic peptides neuropeptide Y (NPY), and agouti-related protein (AGRP) mRNA were assessed by RT-qPCR. The blood samples of control, model and high dose LJZD groups were analyzed by metabolomic. RESULTS: Network pharmacology highlighted the IL-6/leptin mediated JAK-STAT signaling pathway, which regulated downstream anorexigenic and orexigenic peptides in hypothalamus. LJZD ameliorated CIA via stimulating food intake and water consumption in rats. Cisplatin-induced gastric antrum, liver, ileum injuries were ameliorated, serum leptin level reduction was elevated, and ghrelin, IL-6, GDF15 level increases were decreased after LJZD treatments. In gastric antrum and hypothalamus, LJZD inhibited cisplatin-induced activation of JAK-STAT signaling pathway, downregulated the transcriptions of downstream anorexigenic peptides CART, POMC, TRH, and upregulated orexigenic peptides NPY, AGRP in hypothalamus. Importantly, the effect of LJZD in treating CIA might partly relate to the improvements of 23 abnormal metabolites. CONCLUSION: This study implies that inhibiting JAK-STAT signaling pathway, regulating the expressions of anorexigenic and orexigenic peptides, and mediating various metabolic pathways might be potential mechanisms of LJZD's effect against CIA.

Ferulic acid, a phytochemical with transient anorexigenic effects in birds.

Ferulic acid (FA) is a phenolic acid found within the plant cell wall that has physiological benefits as an antioxidant. Although metabolic benefits of FA supplementation are described, lacking are reports of effects on appetite regulation. Thus, our objective was to determine if FA affects food or water intake, using chicks as a model. At 4 days post-hatch, broiler chicks were intraperitoneally injected with 0 (vehicle), 12.5, 25, or 50 mg/kg of FA. Chicks treated with 50 mg/kg of FA consumed 70% less food than controls at 30 min post-injection, and the effect dissipated thereafter. Water intake was not affected at any time. In a behavior analysis, FA-treated chicks defecated fewer times than vehicle-injected chicks, while other behaviors were not affected. There was an increase in c-Fos immunoreactivity within the hypothalamic arcuate nucleus (ARC) of FA-treated chicks, and no differences were detected in other nuclei. mRNA abundance was measured in the whole hypothalamus and the ARC. There was decreased hypothalamic galanin, ghrelin, melanocortin receptor 3, and pro-opiomelanocortin (POMC) mRNA in FA-treated chicks. Within the ARC, there was an increase in c-Fos mRNA and a decrease in POMC mRNA in response to FA. It is likely that the mechanism responsible for mediating FA's transient effects on food intake originates within the ARC, possibly involving POMC. A greater understanding of the short-term, mild appetite-suppressive effects of FA may have applications to treating eating disorders and modulating food intake in animal models of obesity.

The anorexigenic effect of neuropeptide AF in Japanese quail, Coturnix japonica, is associated with activation of the melanocortin system.

Neuropeptide AF (NPAF) decreases food and water intake in birds and food intake in mammals. In this study, the objective was to determine the effects of centrally administered NPAF on food and water intake, hypothalamic c-Fos immunoreactivity and hypothalamic mRNA abundance of appetite-regulating factors in Japanese quail (Coturnix japonica). Seven days post hatch, 6 h fasted quail were intracerebroventricularly (ICV) injected with 0 (vehicle), 4, 8, or 16 nmol of NPAF and food and water intake were measured at 30 min intervals for 180 min. In Experiment 1, chicks which received 4, 8, and 16 nmol ICV NPAF had reduced food intake for 120, 60 and 180 min following injection, respectively, and reduced water intake during the entire 180 min observation. In Experiment 2, there was increased c-Fos immunoreactivity in the paraventricular nucleus, the ventromedial nucleus of the hypothalamus, and the dorsomedial hypothalamic nucleus in NPAF-injected quail. In Experiment 3, ICV NPAF was associated with decreased corticotropin-releasing factor mRNA, and an increase in hypothalamic proopiomelanocortin and melanocortin receptor 4 mRNA. These results demonstrate that central NPAF suppresses food and water intake in quail, effects that are likely mediated via the melanocortin system in the hypothalamus.

919 syrup inhibits ROS-mediated leptin-induced anorexia by activating PPARγ and improves gut flora abnormalities.

BACKGROUND: Women with postpartum psychiatric disorders are prone to severe anorexia. Clinical studies have revealed the efficacy of 919 syrup, a traditional Chinese medicine mixture against postpartum illnesses, such as in regulating maternal mood and improving postpartum anorexia. AIM: This study investigated the mechanisms through which 919 syrup improved anorexia induced by postpartum stress, focussing on the combined peroxisome proliferator-activated receptor gamma (PPARγ) and leptin signalling pathway, and its effects on the structure of the gut flora. METHODS: Mice were randomly divided into five groups-control group, immobilisation stressed (IS) group (normal saline), pioglitazone (Piog; western medicine control) group, 919 syrup low-dose (TJD; 13.5 g/kg) group, and 919 syrup high-dose (TJG; 27.0 g/kg) group. The control group was housed normally. The other groups received IS for 3 h daily for 21 days. The treatments were initiated following the first postnatal day and were administered by gastric gavage. All mice were sacrificed under anaesthesia on postnatal day 22. Blood, hypothalamus, stomach, and faecal specimens were collected. Gene and protein expression levels of components of the PPARγ-leptin signalling pathway in the serum, hypothalamus, and stomach were determined. Immunofluorescence staining for proopiomelanocortin (POMC), phosphorylated signal transducer and activator of transcription 3 (pSTAT3), and leptin was performed to observe their spatial distributions in the hypothalamus and stomach. 16s rRNA gene sequencing and bioinformatics analysis of fecal specimens were performed. RESULTS: After IS, postpartum mice showed significantly reduced appetite and body weight, accompanied by abnormalities in the structure of the gut flora. Treatment with 919 syrup (27.0 g/kg) downregulated malondialdehyde and upregulated catalase, glutathione peroxidase, and superoxide dismutase by activating PPARγ, thereby affecting the expression of leptin signalling pathway components (leptin, leptin receptor, pSTAT3, POMC, and cocaine and amphetamine-related transcript and neuropeptide Y), and modulated the gut flora in stressed mice. CONCLUSION: 919 syrup improved appetite in mice with postnatal stress by activating PPARγ to induce crosstalk with the leptin signalling pathway, this mechanism was similar to that of PPARγ agonists. 919 syrup also improved gut flora structure, and the changes in the relative abundances of the gut flora strongly correlated with the expression levels of PPARγ and leptin pathway components.

Antagonism for NPY signaling reverses cognitive behavior defects induced by activity-based anorexia in mice.

Patients with AN often express psychological symptoms such as body image distortion, cognitive biases, abnormal facial recognition, and deficits in working memory. However, the molecular mechanisms underlying the impairment of cognitive behaviors in AN remain unknown. In the present study, we measured cognitive behavior using novel object recognition (NOR) tasks and mRNA expressions in hypothalamic neuropeptides in female C57BL/6J mice with activity-based anorexia (ABA). Additionally, we evaluated the effects of antagonists with intracerebroventricular (icv) administration on the impairment of cognitive behavior in NOR tasks. Our results showed that NOR indices were lowered, subsequently increasing mRNA levels of agouti-related peptide (AgRP) and neuropeptide Y (NPY), and c-Fos- and AgRP- or NPY-positive cells in the hypothalamic arcuate nucleus in ABA mice. We also observed that icv administration of anti-NPY antiserum (2 µl), anti-AgRP antibody (0.1 µg), and Y5 receptor antagonist CPG71683 (15 nmol) significantly reversed the decreased NOR indices. Therefore, our results suggest that increased NPY and AgRP signaling in the brain might contribute to the impairment of cognitive behavior in AN.

The Effect of Peppermint (Mentha piperita) Extract on the Severity of Nausea, Vomiting and Anorexia in Patients with Breast Cancer Undergoing Chemotherapy: A Randomized Controlled Trial.

Background and Objective: Nausea, vomiting, and anorexia are the most common side effects reported in cancer patients undergoing chemotherapy. The present study aimed to determine the effect of peppermint extract on the severity of nausea, vomiting, and anorexia in patients with breast cancer undergoing chemotherapy. Methods and Materials: In this randomized controlled trial, we selected 84 patients with breast cancer undergoing chemotherapy. They were then assigned to 2 groups of experimental and control (n = 42, each) using block randomization. Patients in the experimental group received 40 drops of peppermint extract mixed in 20 cc of tap water every 8 hours, while patients in the control group received 40 drops of distilled water mixed in 20 cc of tap water every 8 hours. The severity of nausea, vomiting, and anorexia was measured and recorded before the intervention, and immediately, 24 and 48 hours after the chemotherapy using the Visual Analogue Scale. Statistical analysis of the data was conducted using SPSS software version 21. Results: The results of the present study revealed that there was a significant difference between the 2 groups at 24 and 48 hours after the chemotherapy (P < .05), so that the mean score of the severity of nausea, vomiting, and anorexia in the experimental group was lower than in the control group (P < .05). Conclusion: The use of peppermint as a method in complementary medicine may improve nausea, vomiting, and anorexia in patients with breast cancer undergoing chemotherapy. Further studies with greater sample size and longer follow-up period are needed to confirm the current findings.

Omega-3 offers better hypothalamus protection by decreasing POMC expression and elevating ghrelin hormone: a prospective trial to overcome methotrexate-induced anorexia.

PURPOSE: Methotrexate (MTX) therapy is widely used in treatment of different types of diseases including inflammatory diseases, autoimmune disorders, and cancer. However, most of patients respond well to MTX, they suffer from multiple side effects including severe anorexia. Omega-3 fatty acid possesses many beneficial biological activities. Therefore, the objective of our study is to explore the effect of the combined modality of omega-3 (400 mg/kg/day) in MTX-induced anorexia in rats. METHODS: The effect of MTX alone and in combination with omega-3 on the body weight, ghrelin hormone level, histopathological findings of taste buds and hypothalamus and POMC gene expression were investigated. RESULTS: Interestingly, the capability of omega-3 to overcome the anorexic effect of MTX could be manifested by controlling weight loss, increasing serum HDL, elevating the ghrelin level as well as reducing both lesions within taste buds and hypothalamus and hypothalamic POMC gene expression. CONCLUSIONS: our findings revealed that the omega-3 might be used as a complementary supplement during the MTX therapy to ameliorate its anorexic effect.

The effect of Benson's relaxation response on sleep quality and anorexia in cancer patients undergoing chemotherapy: A randomized controlled trial.

BACKGROUND AND OBJECTIVES: Patients with cancer experience many side effects due to its nature and usual treatments. Sleep disorders and anorexia are the most commonly reported symptoms in cancer patients undergoing chemotherapy. The present study aimed to investigate the effect of Benson's Relaxation Response (BRR) on sleep quality and anorexia in cancer patients undergoing chemotherapy. METHODOLOGY AND PARTICIPANTS: In the present clinical trial, a total of 84 patients were enrolled and randomly divided into two groups of experimental and control. Benson's relaxation response was administered to the experimental group twice a day over 5 consecutive days. Data was collected using St. Mary's Hospital Sleep Questionnaire (SMHSQ) and anorexia questionnaire with Visual Analog Scale (VAS). RESULTS: The results of our study showed a significant improvement in the sleep quality in the experimental group at 24 (p = 0.02) and 48 (p = 0.001) hours after the intervention compared to the control group. Benson's relaxation response (BRR) also had a significant effect on the anorexia in the experimental group at 24 (7.5 ± 1.6) and 48 (6.9 ± 2.1) hours after the intervention compared to the control group. No side effects were reported during the study and follow-up period. CONCLUSION: Benson's relaxation response as a complementary method may improve sleep quality and anorexia in cancer patients undergoing chemotherapy. Further studies with greater sample size and longer follow-up period are needed to confirm the current findings.

Anorexigenic effects of substance P in Coturnix japonica.

Substance P (SP) is an 11-amino acid tachykinin-related peptide that has anorexigenic effects in birds and mammals although the central mechanism is not well understood. Hence, the objective was to identify appetite-associated hypothalamic mechanisms in Japanese quail (Coturnix japonica). Seven days post-hatch, quail were intracerebroventricularly injected with 0, 0.25, 0.5 or 1.0 nmol of SP and monitored for 180 min. On a cumulative basis, quail that received 0.5 and 1.0 nmol of SP consumed less food for 90 min post-injection. On a non-cumulative basis, food intake was reduced in 0.5 nmol-injected birds at 30 min post-injection. Water intake was not affected. A comprehensive behavior analysis was performed, revealing that SP-injected chicks displayed less feeding pecks and reduced locomotion compared to vehicle-injected birds. To identify molecular mechanisms, the hypothalamus was isolated at 1 h post-injection and real-time PCR was performed to measure mRNA. Agouti-related peptide (AgRP) mRNA was reduced in SP-injected chicks. Immunohistochemistry was used to quantify c-Fos-expressing cells in appetite-associated hypothalamic nuclei. There were more reactive cells in the lateral hypothalamus (LH) and the paraventricular nucleus (PVN) of SP- than vehicle-injected chicks. The LH and PVN were collected for gene expression analysis. Corticotropin-releasing factor (CRF) and urotensin 2 (UTS2) mRNAs were greater in SP- than vehicle-injected chicks in the PVN. In the LH, CRF receptor sub-type 2 (CRFR2) mRNA was greater and kappa opioid receptor mRNA was reduced in SP- compared to vehicle-injected quail. Thus, SP induces a potent anorexia in quail that coincides with increased LH-specific CRFR2 mRNA and increased UTS2 mRNA in the PVN. Future studies will evaluate whether SP-induced anorexigenic effects are mediated through CRF receptors.

Modified Liujunzi Decoction () Alleviates Chemotherapy-Induced Anorexia in Advanced Non-Small Cell Lung Cancer: A Propensity Score Matched Case-Control Study.

OBJECTIVE: To evaluate the effect of Chinese herbal medicine formula, modified Liujunzi Decoction (, MLJZT), for anorexia, utilized as adjunct therapy during chemotherapy treatment for patients with advanced non-small cell lung cancer (NSCLC). METHODS: The study adopted a propensity score-matched design based on a prospective database. From February 2016 to September 2017, patients with advanced NSCLC that received both cisplatin-based chemotherapy and MLJZT (IM group) were 1:1 propensity score-matched to patients that received the cisplatin-based chemotherapy alone (control group). Changes in anorexia and weight, as well as side effects were evaluated per week within 4-cycle chemotherapy. RESULTS: Overall, 156 patients with advanced NSCLC that had received chemotherapy from our database were identified and 53 pairs were matched successfully. In total, 48.6% (50/53) of patients in the IM group had anorexia-improvement compared to 28.3% (15/53) of patients in the control group, and a total of 39.6% (21/53) of patients in the control group had a worsening of anorexia compared to only 7.8% (8/53) of patients in the IM group (P<0.01). The weight reduced significantly over time in the control group (-2.36 ± 2.53 kg) as compared to the IM group (-0.62 ± 3.89 kg, P<0.01). CHM didn't reduce the efficacy of chemotherapy in shrinking tumor size, and didn't increase the incidence of side effects such as hematological and hepatorenal toxicity. CONCLUSION: MLJZT is effective and safe for alleviating anorexia in patients with NSCLC. These findings warrant the conduct of a randomized controlled trial.

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

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-HT2C and 5-HT3 ), 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-HT3 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 cisplatin-induced anorexia rats. CONCLUSIONS AND INFERENCES: D-methionine supplementation prevents cisplatin-induced 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.

Prospective, randomized, cross-over pilot study of the effects of Rikkunshito, a Japanese traditional herbal medicine, on anorexia and plasma-acylated ghrelin levels in lung cancer patients undergoing cisplatin-based chemotherapy.

Purpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer. Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5 g/day for 14 days (Group A, N = 20) or not (Group B, N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and aprepitant regardless of group assignment. Rescue drugs were allowed as required. The primary and key secondary endpoints were changes in caloric intake and in plasma acylated ghrelin (AG) levels, respectively. Average daily caloric intake during days 3 to 5 was compared with that on day 1 of each course. Results The primary and key secondary endpoints were analyzed in 31 patients (per protocol population) completing the study. Reduction rate of caloric intake was lower in RKT, than in control courses (18% vs. 25%, P = 0.025). Plasma AG levels significantly declined between days 1 and 3 in RKT (12.3 vs. 7.5 fmol/mL, P < 0.001) and control (10.8 vs. 8.6 fmol/mL, P < 0.001) courses. However, those obviously increased to 8.5 fmol/mL (P = 0.025) by day 5 in RKT course but not in control course (7.7 fmol/mL, P = 0.28). Conclusions Rikkunshito could mitigate CIA and ameliorate plasma AG levels during the delayed phase of CDDP-based chemotherapy in lung cancer patients. Clinical trial registration numbers: UMIN000010748.

Efficacy of oral administration of cystine and theanine in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery: a multi-institutional, randomized, double-blinded, placebo-controlled, phase II trial (JORTC-CAM03).

PURPOSE: Capecitabine-based adjuvant chemotherapy for colorectal cancer patients often causes adverse events (AEs), such as diarrhea, stomatitis, anorexia, and hand-foot syndrome (HFS). Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and hence are also expected to attenuate capecitabine-induced AEs. Therefore, we aimed to investigate the safety and efficacy of cystine/theanine treatment in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery. METHODS: A total of 100 colorectal cancer patients treated with capecitabine as an adjuvant chemotherapy after surgery were randomly allocated into the cystine/theanine group (n = 52) or the placebo group (n = 48). The primary endpoint was incidence rate of diarrhea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints included incidence rates of other AEs (CTCAE v.4.0-JCOG), as well as the incidence rate of HFS according to the HFS grading scale. RESULTS: There were no significant differences in capecitabine-induced AEs between the two groups. However, the incidence rate of diarrhea of grade 1 or higher tended to be lower in the cystine/theanine group than the placebo group (18.4% vs. 28.9%, p = 0.169) as well as the incidence rate of HFS of grade 1 or higher (CTCAE v.4.0-JCOG or HFS grading scale) (67.4% vs. 77.8%, p = 0.185, 67.3% vs. 80.0%, p = 0.124, respectively). CONCLUSION: This trial demonstrated that cystine/theanine treatment of colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery is safe and has the tendency to reduce the incidence rate of diarrhea or HFS. TRIAL REGISTRATION: UMIN000024784.

Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice.

Peripheral lipopolysaccharide (LPS) injection induces systemic inflammation through the activation of the inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK)/NF-κB signaling pathway, which promotes brain dysfunction resulting in conditions including anorexia. LPS-mediated reduction of food intake is associated with activation of NF-κB signaling and phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. We recently reported phospholipase C-related catalytically inactive protein (PRIP) as a new negative regulator of phosphatidylinositol 3-kinase/AKT signaling. AKT regulates the IKK/NF-κB signaling pathway; therefore, this study aimed to investigate the role of PRIP/AKT signaling in LPS-mediated neuroinflammation-induced anorexia. PRIP gene (Prip1 and Prip2) knockout (Prip-KO) mice intraperitoneally (ip) administered with LPS exhibited increased anorexia responses compared with wild-type (WT) controls. Although few differences were observed between WT and Prip-KO mice in LPS-elicited plasma pro-inflammatory cytokine elevation, hypothalamic pro-inflammatory cytokines were significantly upregulated in Prip-KO rather than WT mice. Hypothalamic AKT and IKK phosphorylation and IκB degradation were significantly increased in Prip-KO rather than WT mice, indicating further promotion of AKT-mediated NF-κB signaling. Consistently, hypothalamic STAT3 was further phosphorylated in Prip-KO rather than WT mice. Furthermore, suppressor of cytokine signaling 3 (Socs3), a negative feedback regulator for STAT3 signaling, and cyclooxogenase-2 (Cox2), a candidate molecule in LPS-induced anorexigenic responses, were upregulated in the hypothalamus in Prip-KO rather than WT mice. Pro-inflammatory cytokines were upregulated in hypothalamic microglia isolated from Prip-KO rather than WT mice. Together, these findings indicate that PRIP negatively regulates LPS-induced anorexia caused by pro-inflammatory cytokine expression in the hypothalamus, which is mediated by AKT-activated NF-κB signaling. Importantly, hypothalamic microglia participate in this PRIP-mediated process. Elucidation of PRIP-mediated neuroinflammatory responses may provide novel insights into the pathophysiology of many brain dysfunctions.

Electro-Acupuncture Alleviates Cisplatin-Induced Anorexia in Rats by Modulating Ghrelin and Monoamine Neurotransmitters.

Anorexia is common in patients with cancer, mostly as a side effect of chemotherapy. The effect of electro-acupuncture (EA) on ameliorating cancer-related symptoms have been studied in animal models and in clinical trials. The aim of this study was to determine optimal conditions for the application of EA to alleviate anorexia, followed by the study of molecular mechanisms affecting its therapeutics. Anorexia was induced in male Wistar rats by injecting cisplatin, which was then followed by EA treatment at CV12, the acupuncture point located in the center of the abdominal midline. Body weight and food intake were measured daily throughout the duration of the study. The levels of monoamine neurotransmitters in the plasma were quantitatively analyzed by HPLC-ECD. Gastrointestinal hormone concentrations were elucidated with ELISA kits. RT-qPCR was performed to evaluate the mRNA expression of ghrelin (GHRL), neuropeptide Y (NPY), and pro-opiomelanocortin. The expression of c-Fos in the nucleus tractus solitarii was detected using western blotting analysis. The optimal conditions of EA to alleviate anorexia in rats was determined to be 1 unit for intensity and 10 Hz for frequency. EA treatment at CV12 reduced the levels of plasma monoamine neurotransmitters 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, dopamine, and norepinephrine; as well as stimulated the expression of GHRL and NPY to alleviate cisplatin-induced anorexia in rats. EA stimulation at CV12 could be used to treat cisplatin-induced anorexia in rats.

Hypothalamic mechanisms associated with neuropeptide K-induced anorexia in Japanese quail (Coturnix japonica).

Central administration of neuropeptide K (NPK), a 36-amino acid peptide, is associated with anorexigenic effects in rodents and chickens. The mechanisms underlying the potent anorexigenic effects of NPK are still poorly understood. Thus, the aim of the present study was to identify the hypothalamic nuclei and neuropeptides that mediate anorexic effects of NPK in 7 day-old Japanese quail (Coturnix japonica). After a 6 h fast, intracerebroventricular (ICV) injection of NPK decreased food and water intake for 180 min post-injection. Quail injected with NPK had more c-Fos immunoreactive cells in the arcuate nucleus (ARC), lateral hypothalamus, and paraventricular nucleus (PVN) compared to the birds that were injected with the vehicle. In the ARC of NPK-injected quail, there was decreased neuropeptide Y (NPY), NPY receptor sub-type 1, and agouti-related peptide mRNA, and increased CART, POMC, and neurokinin receptor 1 mRNA. NPK-injected quail expressed greater amounts of corticotropin-releasing factor (CRF), CRF receptor sub-type 2, melanocortin receptors 3 and 4, and urocortin 3 mRNA in the PVN. In conclusion, results provide insights into understanding NPK-induced changes in hypothalamic physiology and feeding behavior, and suggest that the anorexigenic effects of NPK involve the ARC and PVN, with increased CRF and melanocortin and reduced NPY signaling.