Department of Biology, The City College of New York, New York, NY, 10031, USA.
The Graduate Center of The City University of New York, New York, NY, 10016, USA.
Mol Neurobiol. 2019 Oct;56(10):7159-7172. doi: 10.1007/s12035-019-1589-z. Epub 2019 Apr 15.
Increasing evidence indicates that chemotherapy results in long-term effects on cognitive dysfunction in some cancer survivors. While many studies have established the domains of cognition and corresponding regions in the brain most affected, little is revealed about the potential molecular mechanisms that mediate these adverse changes after treatment. The effects of chemotherapy on the brain are likely attributed to various mechanisms, including oxidative stress and immune dysregulation, features that are also reminiscent of cognitive aging. We have investigated the cognitive effects of a cocktail composed of doxorubicin and cyclophosphamide (AC-chemo) in a surgical ovariectomized rodent model. In this study, we address whether the levels of pro-inflammatory cytokines and oxidative stress-responsive gene markers are altered in the CNS of rats treated with systemic AC-chemo. We further evaluated the levels of nucleic acids modified by oxidative stress in the hippocampus using both immunohistochemical and Northern blotting techniques with a monoclonal antibody against 8-hydroxyguanosine (8-OHG) and 8-OHdG base lesions. We demonstrate that ERK 1/2 and JNK/SAPK signaling activities are elevated in the hippocampus of AC-chemo rats. The levels of pro-inflammatory, oxidative stress-responsive, and RNA/DNA damage markers were also higher in drug-injected animals relative to saline controls. The results indicate that the effects of AC chemotherapy are associated with oxidative damage and a global stress response in the hippocampus. These alterations in the molecular signature of the brain may underlie the processes that contribute to cognitive impairment after treatment.
越来越多的证据表明，化疗会导致某些癌症幸存者长期出现认知功能障碍。虽然许多研究已经确定了受影响最严重的认知领域和相应的大脑区域，但对于治疗后介导这些不良变化的潜在分子机制却知之甚少。化疗对大脑的影响可能归因于多种机制，包括氧化应激和免疫失调，这些特征也与认知衰老相似。我们研究了阿霉素和环磷酰胺（AC-化疗）鸡尾酒在手术去卵巢啮齿动物模型中的认知影响。在这项研究中，我们研究了全身接受 AC-化疗的大鼠中枢神经系统中促炎细胞因子和氧化应激反应基因标志物的水平是否发生改变。我们还使用针对 8-羟基鸟嘌呤（8-OHG）和 8-OHdG 碱基损伤的单克隆抗体，通过免疫组织化学和 Northern 印迹技术进一步评估了氧化应激修饰的核酸在海马体中的水平。我们证明，ERK 1/2 和 JNK/SAPK 信号转导活性在 AC-化疗大鼠的海马体中升高。与生理盐水对照组相比，药物注射动物的促炎、氧化应激反应和 RNA/DNA 损伤标志物的水平也更高。结果表明，AC 化疗的作用与海马体中的氧化损伤和整体应激反应有关。这些大脑分子特征的改变可能是导致治疗后认知障碍的过程的基础。
