Elevated Oxidative Stress and DNA Damage in Cortical Neurons of Chemotherapy Patients.
Elevated Oxidative Stress and DNA Damage in Cortical Neurons of Chemotherapy Patients.
复制标题
化疗患者皮质神经元氧化应激升高和 DNA 损伤。
DOI：
10.1093/jnen/nlab074
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发表时间：
2021
影响因子：
3.2
通讯作者：
Feany,MelB
中科院分区：
文献类型：
--
作者：
Torre,Matthew;Dey,Adwitia;Woods,JaredK;Feany,MelB
化疗的非预期神经系统后遗症导致患者发病率显著增加。在高达80%的接受化疗的癌症患者中观察到化疗相关的认知障碍（CRCI），并且涉及多个认知领域，包括执行功能。CRCI的病理生理学基础和化疗的神经毒性尚不完全清楚，但根据临床前数据，氧化应激和DNA损伤是非常合理的机制。不幸的是，在人类中验证与CRCI相关的通路受到缺乏患者脑组织相关神经病理学研究的限制。在本研究中，我们对接受化疗的癌症患者（n = 15）、未接受化疗的癌症患者（n = 10）和无癌症病史的患者（n = 10）的额叶尸检组织切片进行氧化应激（硝基酪氨酸、4-羟基壬烯醛）和DNA损伤（pH 2AX、pATM）标记物染色。与对照组相比，接受化疗的癌症患者额叶皮质神经元中氧化应激和DNA损伤标记物的染色增加。我们检测到在最后一次化疗和死亡之间的持续时间在氧化应激和DNA损伤方面没有统计学显著差异。该研究强调了氧化应激和DNA损伤在CRCI病理生理学和化疗神经毒性中的潜在相关性。
The unintended neurologic sequelae of chemotherapy contribute to significant patient morbidity. Chemotherapy-related cognitive impairment (CRCI) is observed in up to 80% of cancer patients treated with chemotherapy and involves multiple cognitive domains including executive functioning. The pathophysiology underlying CRCI and the neurotoxicity of chemotherapy is incompletely understood, but oxidative stress and DNA damage are highly plausible mechanisms based on preclinical data. Unfortunately, validating pathways relevant to CRCI in humans is limited by an absence of relevant neuropathologic studies of patient brain tissue. In the present study, we stained sections of frontal lobe autopsy tissue from cancer patients treated with chemotherapy (n = 15), cancer patients not treated with chemotherapy (n = 10), and patients without history of cancer (n = 10) for markers of oxidative stress (nitrotyrosine, 4-hydroxynonenal) and DNA damage (pH2AX, pATM). Cancer patients treated with chemotherapy had increased staining for markers of oxidative stress and DNA damage in frontal lobe cortical neurons compared to controls. We detected no statistically significant difference in oxidative stress and DNA damage by the duration between last administration of chemotherapy and death. The study highlights the potential relevance of oxidative stress and DNA damage in the pathophysiology of CRCI and the neurotoxicity of chemotherapy.