Department of Adult Health, Wayne State University, Detroit, MI 48202, USA.
BMC Neurosci. 2011 Dec 9;12:124. doi: 10.1186/1471-2202-12-124.
In this study, we examined the effects of cyclophosphamide, methothrexate, and 5-Fluorouracil (CMF) drug combination on various aspects of learning and memory. We also examined the effects of CMF on cell proliferation and chromatin remodeling as possible underlying mechanisms to explain chemotherapy-associated cognitive dysfunction. Twenty-four adult female Wistar rats were included in the study and had minimitter implantation for continuous activity monitoring two weeks before the chemotherapy regimen was started. Once baseline activity data were collected, rats were randomly assigned to receive either CMF or saline injections given intraperitoneally. Treatments were given once a week for a total of 4 weeks. Two weeks after the last injection, rats were tested in the water maze for spatial learning and memory ability as well as discrimination learning. Bromodeoxyuridine (BrdU) injection was given at 100 mg/Kg intraperitoneally 4 hours prior to euthanasia to determine hippocampal cell proliferation while histone acetylation and histone deacetylase activity was measured to determine CMF effects on chromatin remodeling.
Our data showed learning and memory impairment following CMF administration independent of the drug effects on physical activity. In addition, CMF-treated rats showed decreased hippocampal cell proliferation, associated with increased histone acetylation and decreased histone deacetylase activity.
These results suggest the negative consequences of chemotherapy on brain function and that anti-cancer drugs can adversely affect the self-renewal potential of neural progenitor cells and also chromatin remodeling in the hippocampus. The significance of our findings lie on the possible usefulness of animal models in addressing the clinical phenomenon of 'chemobrain.'
在这项研究中，我们研究了环磷酰胺、甲氨蝶呤和 5-氟尿嘧啶（CMF）药物联合对学习和记忆各个方面的影响。我们还研究了 CMF 对细胞增殖和染色质重塑的影响，作为解释化疗相关认知功能障碍的潜在机制。将 24 只成年雌性 Wistar 大鼠纳入研究，并在开始化疗方案前两周进行 minimitter 植入以进行连续活动监测。一旦收集到基线活动数据，大鼠就被随机分配接受 CMF 或生理盐水腹腔内注射。每周治疗一次，共 4 周。最后一次注射后两周，大鼠在水迷宫中进行空间学习和记忆能力以及辨别学习测试。在安乐死前 4 小时，以 100mg/kg 腹腔内注射溴脱氧尿苷（BrdU），以确定海马细胞增殖，同时测量组蛋白乙酰化和组蛋白去乙酰化酶活性，以确定 CMF 对染色质重塑的影响。
我们的数据表明，CMF 给药后会出现学习和记忆障碍，而与药物对身体活动的影响无关。此外，CMF 治疗的大鼠表现出海马细胞增殖减少，与组蛋白乙酰化增加和组蛋白去乙酰化酶活性降低有关。
这些结果表明化疗对大脑功能的负面影响，以及抗癌药物可能会对神经祖细胞的自我更新潜力和海马体中的染色质重塑产生不利影响。我们研究的意义在于动物模型在解决“化疗脑”这一临床现象方面的可能有用性。
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