Abstract
Cancer chemotherapy is commonly accompanied by mucositis, anorexia, weight loss, and anxiety independently from cancer-induced anorexia-cachexia, further aggravating clinical outcome. Ghrelin is a peptide hormone produced in gastric mucosa that reaches the brain to stimulate appetite. In plasma, ghrelin is protected from degradation by ghrelin-reactive immunoglobulins (Ig). To analyze possible involvement of ghrelin in the chemotherapy-induced anorexia and anxiety, gastric ghrelin expression, plasma levels of ghrelin, and ghrelin-reactive IgG were studied in rats treated with methotrexate (MTX). Rats received MTX (2.5 mg/kg, subcutaneously) for three consecutive days and were killed 3 days later, at the peak of anorexia and weight loss. Control rats received phosphate-buffered saline. Preproghrelin mRNA expression in the stomach was analyzed by in situ hybridization. Plasma levels of ghrelin and ghrelin-reactive IgG were measured by immunoenzymatic assays and IgG affinity kinetics by surface plasmon resonance. Anxiety- and depression-like behaviors in MTX-treated anorectic and in control rats were evaluated in the elevated plus-maze and the forced-swim test, respectively. In MTX-treated anorectic rats, the number of preproghrelin mRNA-producing cells was found increased (by 51.3%, p < 0.001) as well were plasma concentrations of both ghrelin and des-acyl-ghrelin (by 70.4%, p < 0.05 and 98.3%, p < 0.01, respectively). In contrast, plasma levels of total IgG reactive with ghrelin and des-acyl-ghrelin were drastically decreased (by 87.2 and 88.4%, respectively, both p < 0.001), and affinity kinetics of these IgG were characterized by increased small and big Kd, respectively. MTX-treated rats displayed increased anxiety- but not depression-like behavior. MTX-induced anorexia, weight loss, and anxiety are accompanied by increased ghrelin production and by a decrease of ghrelin-reactive IgG levels and affinity binding properties. Such changes of ghrelin-reactive IgG may underlie their decreased ghrelin-transporting capacities compromising ghrelin orexigenic and anxiolytic effects and contributing to chemotherapy-induced loss of appetite.
Highlights
Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting, and psychological distress and is a major source of increased morbidity and mortality in cancer patients [1]
In our laboratory, a rat model of MTX chemotherapy characterized by anorexia, cachexia, intestinal mucositis, impairment of absorption and digestive functions, alteration of the gut barrier, and diarrhea [27,28,29,30]
The number of preproghrelin mRNA-producing cells was increased by 51.3% in MTX-treated rats as compared to controls (Figure 2C)
Summary
Cancer anorexia–cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting, and psychological distress and is a major source of increased morbidity and mortality in cancer patients [1]. Des-acyl ghrelin is the main form of the circulating peptide, it has no orexigenic effect [14]. To this day, ghrelin is the only known peripheral factor stimulating appetite, but it is a pleiotropic hormone with multiple functions [15], including modulating mood and emotion [16]. Cancer chemotherapy is commonly accompanied by mucositis, anorexia, weight loss, and anxiety independently from cancer-induced anorexia–cachexia, further aggravating clinical outcome. To analyze possible involvement of ghrelin in the chemotherapy-induced anorexia and anxiety, gastric ghrelin expression, plasma levels of ghrelin, and ghrelin-reactive IgG were studied in rats treated with methotrexate (MTX)
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