Malik N M, Moore G B T, Smith G, Liu Y-L, Sanger G J, Andrews P L R
Division of Basic Medical Sciences, St. George's University of London, London, SWl7 ORE, Harlow, Essex CMl9 5AW, UK.
Pharmacol Biochem Behav. 2006 Jan;83(1):9-20. doi: 10.1016/j.pbb.2005.11.017. Epub 2006 Jan 26.
Many cancer patients receiving chemotherapy experience fatigue, disturbed circadian rhythms, anorexia and a variety of dyspeptic symptoms including nausea. There is no animal model for this 'chemotherapy-related malaise' so we investigated the behavioural and molecular effects of a potent chemotherapeutic agent, cisplatin (CP, 6 mg/kg, i.p.) in rats. Dark-phase horizontal locomotor activity declined post-CP reaching a nadir on day 3 (P < 0.001), before recovering after 7 days. CP's effect was most marked in the late part (05.00-07.00) of the dark-phase. Food intake reached a nadir (P > 0.001) at 2 days, coincident with an increase in gastric contents (cisplatin 9.04+/-0.8 vs. saline 2.32+/-0.3 g; P < 0.001). No changes occurred in hypothalamic mRNA expression for AGRP, NPY, HCRT, CRH, IL-1, IL-6, TNFalpha, ABCG1, SLC6A4, PPIA and HPRT mRNA but tryptophan hydroxylase (TPH) mRNA was decreased (47%, P < 0.05) at day 21 post-CP. This shows that despite marked behavioural effects of cisplatin, only a discrete change (TPH) was found in hypothalamic mRNA expression and that occurred when the animals' behaviour had recovered. Findings are discussed in relation to the neuropharmacology of chemotherapy-induced malaise.
许多接受化疗的癌症患者会出现疲劳、昼夜节律紊乱、食欲不振以及包括恶心在内的各种消化不良症状。目前尚无针对这种“化疗相关不适”的动物模型，因此我们研究了一种强效化疗药物顺铂（CP，6毫克/千克，腹腔注射）对大鼠行为和分子的影响。注射CP后，大鼠在黑暗期的水平运动活动下降，在第3天降至最低点（P < 0.001），7天后恢复。CP的作用在黑暗期后期（05:00 - 07:00）最为明显。食物摄入量在第2天降至最低点（P > 0.001），与此同时胃内容物增加（顺铂组9.04±0.8克，生理盐水组2.32±0.3克；P < 0.001）。下丘脑促肾上腺皮质激素释放肽（AGRP）、神经肽Y（NPY）、下丘脑泌素（HCRT）、促肾上腺皮质激素释放激素（CRH）、白细胞介素-1（IL-1）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNFα）、ATP结合盒转运蛋白G1（ABCG1）、溶质载体家族6成员4（SLC6A4）、肽基脯氨酰异构酶A（PPIA）和次黄嘌呤磷酸核糖转移酶（HPRT）的mRNA表达没有变化，但在注射CP后第21天，色氨酸羟化酶（TPH）的mRNA减少（47%，P < 0.05）。这表明，尽管顺铂对行为有显著影响，但在下丘脑mRNA表达中仅发现了一个离散变化（TPH），且该变化发生在动物行为恢复时。本文结合化疗引起不适的神经药理学对研究结果进行了讨论。
