Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications.
Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications.
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DOI：
10.1186/1471-2202-12-124
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发表时间：
2011-12-09
期刊：
影响因子：
2.4
通讯作者：
Woods J
中科院分区：
文献类型：
--
作者：
Briones TL;Woods J
在这项研究中，我们研究了环磷酰胺，甲氨蝶呤，5-氟尿嘧啶（CMF）药物组合对学习和记忆的各个方面的影响。我们还研究了CMF对细胞增殖和染色质重塑的影响，这可能是解释化疗相关认知功能障碍的潜在机制。24只成年雌性Wistar大鼠被纳入研究，并在化疗方案开始前两周植入minimitter进行连续活动监测。一旦收集了基线活动数据，大鼠被随机分配接受CMF或盐水腹腔内注射。每周给药一次，共4周。末次注射后2周，在水迷宫中测试大鼠的空间学习记忆能力以及辨别学习能力。在安乐死前4小时腹膜内给予100 mg/Kg溴脱氧尿苷（BrdU）注射液以测定海马细胞增殖，同时测量组蛋白乙酰化和组蛋白脱乙酰酶活性以测定CMF对染色质重塑的影响。我们的数据显示，CMF给药后的学习和记忆障碍与药物对体力活动的影响无关。此外，CMF处理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脱乙酰酶活性降低相关。这些结果表明化疗对脑功能的负面影响，抗癌药物可能会对神经祖细胞的自我更新潜力以及海马中的染色质重塑产生不利影响。我们的研究结果的意义在于动物模型在解决“化学脑”临床现象中的可能有用性。'
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.'
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DOI：
10.1093/jnci/90.3.210
发表时间：
1998-02-04
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
van Dam, FSAM;Schagen, SB;Rodenhuis, S
通讯作者：
Rodenhuis, S
影响因子：
2.4
作者：
Janelsins, Michelle C.;Roscoe, Joseph A.;Gross, Robert A.
通讯作者：
Gross, Robert A.
影响因子：
11.5
作者：
Lee, GD;Longo, DL;Ingram, DK
通讯作者：
Ingram, DK
影响因子：
45.3
作者：
Ahles, TA;Saykin, AJ;Silberfarb, PM
通讯作者：
Silberfarb, PM
DOI：
10.1073/pnas.0407643101
发表时间：
2004-11-23
影响因子：
11.1
作者：
Hsieh, J;Nakashima, K;Gage, FH
通讯作者：
Gage, FH