Chemotherapy-induced anorexia is accompanied by activation of brain pathways signaling dehydration

Sinno, Maria Hamze; Coquerel, Quentin; Boukhettala, Nabile; Coëffier, Moı̈se; Gallas, Syrine; Terashi, Mutsumi; Ibrahim, Ayman; Breuillé, Denis; Déchelotte, Pierre; Fetissov, Sergueı̈ O.

doi:10.1016/j.physbeh.2010.09.016

Cited by 26 publications

(20 citation statements)

References 69 publications

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“…This finding does not necessarily preclude a role for chemotherapy induced inflammatory processes in the induction of persistent CTRS but it suggests that some factors which drive acute and persistent symptoms are distinct. For instance, acute fatigue, anorexia, and weight loss may be related to systemic dehydration and intestinal permeability since, cytotoxic agents alter gastrointestinal (GI) function by decreasing absorption from the small intestine and increasing GI permeability [36,37]. These symptoms were found to cluster together in colorectal cancer patients undergoing cytotoxic chemotherapy [38].…”

Section: Discussionmentioning

confidence: 99%

The role of IL-1β and TNF-α signaling in the genesis of cancer treatment related symptoms (CTRS): A study using cytokine receptor-deficient mice

Smith

Leo

Anderson

et al. 2014

Brain, Behavior, and Immunity

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Cytotoxic chemotherapeutic agents often induce a cluster of cancer treatment related symptoms (CTRS). The purpose of this study was to develop a mouse model of CTRS to examine the role of IL-1β and TNF-α signaling in the genesis of these symptoms. CTRS (change in wheel running activity, food intake, and body weight from baseline) were examined in wild type (WT) mice or mice lacking the TNF-α p55 (type 1) receptor (TNFR1−/−) and/or IL-1β type 1 receptor (IL-1R1−/−) injected with four doses of cyclophosphamide/Adriamycin/5-fluorouracil (CAF) at 20-day intervals. Inflammatory cytokines in blood and tissues were measured using multiplex immunoassays and quantitative RT-PCR. ANOVA was used to examine differences between genotype and/or treatment group. Kaplan-Meier analysis was used to estimate survival rate. CAF rapidly increased IL-1β and TNF-α signaling in WT mice. CAF induced acute CTRS immediately following drug injection which returned to baseline prior to the next CAF dose. Persistent CTRS were evident 3 weeks after the 4th CAF dose. Acute but not persistent CTRS were associated with increased levels of IL-7, IL-9, KC, MCP-1, GCSF, and IP-10. This CAF induced inflammatory response was blunted in IL-1R1 deficient mice and absent in IL-1R1/TNFR1-deficient mice. IL-1R1−/− mice showed an identical pattern of CTRS to their WT counterparts. The assessment of CTRS in IL-1R1/TNF-R1-deficient mice was precluded by severe toxicity. Our data suggest that an important function of the IL-1β and TNF-α driven inflammatory cascade is to promote recovery following exposure to cytotoxic agents.

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Section: Discussionmentioning

confidence: 99%

The role of IL-1β and TNF-α signaling in the genesis of cancer treatment related symptoms (CTRS): A study using cytokine receptor-deficient mice

Smith

Leo

Anderson

et al. 2014

Brain, Behavior, and Immunity

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“…On day 6, the rats treated with methotrexate actually had an increase in food intake as compared with prechemotherapy values (Le Bricon et al 1995). Three consecutive injections of 2.5 mg/kg methotrexate reduced food and water intake for approximately 5 days that again recovered and slightly rebounded after day 9 (Sinno et al 2010) while 35 mg/kg 5-fluorouracil slightly decreased food intake on the day of injection but increased kaolin ingestion behavior “pica” in rats (Yamamoto et al 2007) which is a model of gastrointestinal discomfort emesis behavior in rats (Takeda et al 1993). Methotrexate can reverse anorexia and low leptin levels in a rat model of adjuvant-induced arthritis (Jurcovicova et al 2009), and injections of methotrexate, 5-fluorouracil, tamoxifen, and combinations of methotrexate with 5-fluorouracil in male (Foley et al 2008; Walker 2010) and female (E.A.…”

Section: Discussionmentioning

confidence: 99%

Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice

et al. 2011

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Rationale A number of cancer chemotherapeutic agents have been associated with a loss of memory in breast cancer patients although little is known of the causality of this effect. Objectives To assess the potential cognitive effects of repeated exposure to chemotherapeutic agents, we administered the selective estrogen receptor modulator tamoxifen or the antimetabolite chemotherapy, methotrexate, and 5-fluorouracil, alone and in combination to mice and tested them in a learning and memory assay. Methods Swiss-Webster male mice were injected with saline, 32 mg/kg tamoxifen, 3.2 or 32 mg/kg methotrexate, 75 mg/kg 5-fluorouracil, 3.2 or 32 mg/kg methotrexate in combination with 75 mg/kg 5-fluorouracil once per week for 3 weeks. On days 23 and 24, mice were tested for acquisition and retention of a nose-poke response in a learning procedure called autoshaping. In addition, the acute effects of tamoxifen were assessed in additional mice in a similar procedure. Results The chemotherapeutic agents alone and in combination reduced body weight relative to saline treatment over the course of 4 weeks. Repeated treatment with tamoxifen produced both acquisition and retention effects relative to the saline-treated group although acute tamoxifen was without effect except at a behaviorally toxic dose. Repeated treatment with methotrexate in combination with 5-fluorouracil produced effects on retention, but the magnitude of these changes depended on the methotrexate dose. Conclusions These data demonstrate that repeated administration of tamoxifen or certain combination of methotrexate and 5-fluorouracil may produce deficits in the acquisition or retention of learned responses which suggest potential strategies for prevention or remediation might be considered in vulnerable patient populations.

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“…Sections were rehydrated in PBS, and treated with PBS-0.3% Triton X100 (Sigma), followed by 5% bovine serum albumin (Sigma) diluted in PBS supplemented with 0.1% Na azide (blocking buffer) during 1 h. Primary polyclonal anti-sera (raised in rabbits) were applied overnight at 4°C; antibodies against Iba-1 (1:2000, Wako Pure Chemical Industries, Osaka, Japan) were used as a marker for microglia and macrophages and a-MSH antisera (1:3000, Bachem); a-MSH anti-sera was previously validated for a-MSH staining (Hamze Sinno et al, 2010;Lucas et al, 2014). After washes with PBS-0.3% Triton, sections were incubated with secondary antibodies.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Chronic delivery of α-melanocyte-stimulating hormone in rat hypothalamus using albumin-alginate microparticles: Effects on food intake and body weight

et al. 2015

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Chemotherapy-induced anorexia is accompanied by activation of brain pathways signaling dehydration

Cited by 26 publications

References 69 publications

The role of IL-1β and TNF-α signaling in the genesis of cancer treatment related symptoms (CTRS): A study using cytokine receptor-deficient mice

The role of IL-1β and TNF-α signaling in the genesis of cancer treatment related symptoms (CTRS): A study using cytokine receptor-deficient mice

Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice

Chronic delivery of α-melanocyte-stimulating hormone in rat hypothalamus using albumin-alginate microparticles: Effects on food intake and body weight

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