Briones Teresita L, Woods Julie, Wadowska Magdalena
Department of Adult Health, Wayne State University, Detroit, MI 48202, USA.
Department of Biobehavioral Health Science, University of Illinois at Chicago, Chicago, IL 60612, USA.
Behav Brain Res. 2015 Feb 15;279:112-22. doi: 10.1016/j.bbr.2014.02.052. Epub 2014 Mar 12.
Here we examined the involvement of insulin-like growth factor 1 (IGF-1) on chemotherapy-induced cognitive impairment. Sixty-four ovariectomized female Sprague-Dawley rats were included in the study and given cyclophosphamide, methothrexate, and 5-fluorouracil (CMF) drug combination or saline (control). CMF was given once a week for 4 weeks. In one experiment, behavioral testing using the cued learning and spontaneous object recognition tasks were performed either: at the end of treatment or 4 weeks after treatment. In another experiment, rats from the chemotherapy and saline groups received either: continuous insulin-like growth factor 1 (IGF-1) or vehicle delivered subcutaneously via osmotic pump for 21 days (started the week after completion of therapy). Bromodeoxyuridine injections were given for 3 consecutive days starting at 2 weeks after completion of chemotherapy to assess the survival of proliferating cells. Increased levels of IGF-1 and activation of its receptor as well as increased activation of Akt and Erk1/2, its downstream signaling pathways was seen immediately after completion of chemotherapy but decreased 4 weeks after treatment. Behavioral testing showed CMF-induced cognitive impairment after completion of therapy and persisted for 4 weeks. We also found that giving IGF-1 significantly increased activation of its receptor, and the Akt and Erk1/2 pathways, and most importantly attenuated chemotherapy-induced cognitive impairment. CMF-induced neuronal apoptosis was also seen and the ratio of surviving cells that proliferate was higher compared to the number of apoptotic cells in the CMF rats given IGF-1. These results suggest that IGF-1 is involved in CMF-induced cognitive impairment by modulating cell death and cell proliferation.
在此，我们研究了胰岛素样生长因子1（IGF-1）在化疗诱导的认知障碍中的作用。64只去卵巢的雌性Sprague-Dawley大鼠被纳入研究，给予环磷酰胺、甲氨蝶呤和5-氟尿嘧啶（CMF）联合药物或生理盐水（对照）。CMF每周给药一次，共4周。在一项实验中，使用线索学习和自发物体识别任务进行行为测试，测试时间为：治疗结束时或治疗后4周。在另一项实验中，化疗组和生理盐水组的大鼠分别接受：通过渗透泵皮下持续给予胰岛素样生长因子1（IGF-1）或载体，持续21天（在治疗完成后的第二周开始）。从化疗结束后2周开始连续3天注射溴脱氧尿苷，以评估增殖细胞的存活情况。化疗结束后立即观察到IGF-1水平升高及其受体激活，以及其下游信号通路Akt和Erk1/2的激活增加，但在治疗后4周下降。行为测试显示，治疗完成后CMF诱导了认知障碍，并持续了4周。我们还发现，给予IGF-1可显著增加其受体以及Akt和Erk1/2信号通路的激活，最重要的是减轻了化疗诱导的认知障碍。还观察到CMF诱导的神经元凋亡，与给予IGF-1的CMF大鼠中的凋亡细胞数量相比，增殖存活细胞的比例更高。这些结果表明，IGF-1通过调节细胞死亡和细胞增殖参与了CMF诱导的认知障碍。
