Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Rouen, France; Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France.
Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, France; Animal Behavior Platform (SCAC), Rouen, France.
Front Nutr. 2016 Jul 26;3:23. doi: 10.3389/fnut.2016.00023. eCollection 2016.
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.
癌症化疗常伴有黏膜炎、厌食、体重减轻和焦虑，这些症状独立于癌症引起的厌食-恶病质之外，进一步加重了临床结局。胃饥饿素是一种在胃黏膜中产生的肽类激素，它可以到达大脑刺激食欲。在血浆中，胃饥饿素被胃饥饿素反应性免疫球蛋白（Ig）保护免于降解。为了分析胃饥饿素是否参与化疗引起的厌食和焦虑，我们研究了接受甲氨蝶呤（MTX）治疗的大鼠的胃饥饿素表达、血浆胃饥饿素水平和胃饥饿素反应性 IgG。
大鼠连续 3 天接受 MTX（2.5mg/kg，皮下注射），第 3 天处死，此时处于厌食和体重减轻的高峰期。对照组大鼠接受磷酸盐缓冲盐水。通过原位杂交分析胃内 preproghrelin mRNA 的表达。通过免疫酶联测定法测量血浆胃饥饿素和胃饥饿素反应性 IgG 的水平，并通过表面等离子体共振测量 IgG 亲和力动力学。在高架十字迷宫和强迫游泳试验中评估 MTX 治疗的厌食大鼠和对照组大鼠的焦虑和抑郁样行为。
在 MTX 治疗的厌食大鼠中，发现 preproghrelin mRNA 产生细胞的数量增加（增加 51.3%，p<0.001），同时血浆中胃饥饿素和去酰基胃饥饿素的浓度也增加（增加 70.4%，p<0.05 和 98.3%，p<0.01）。相反，与胃饥饿素和去酰基胃饥饿素反应的总 IgG 水平明显降低（分别降低 87.2%和 88.4%，均 p<0.001），并且这些 IgG 的亲和力动力学表现为小 Kd 和大 Kd 增加。MTX 治疗的大鼠表现出焦虑增加，但无抑郁样行为。
MTX 诱导的厌食、体重减轻和焦虑伴随着胃饥饿素产生增加和胃饥饿素反应性 IgG 水平降低以及亲和力结合特性降低。这种胃饥饿素反应性 IgG 的变化可能导致其转运胃饥饿素的能力降低，从而削弱了胃饥饿素的开胃和抗焦虑作用，并导致化疗引起的食欲丧失。
