Chemotherapy-induced cognitive impairment: focus on the intersection of oxidative stress and TNFα.
Chemotherapy-induced cognitive impairment: focus on the intersection of oxidative stress and TNFα.
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DOI：
10.1007/s00018-021-03925-4
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发表时间：
2021-10
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--
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化疗引起的认知障碍(CiCi)在很大一部分癌症幸存者中被观察到。尽管许多化疗药物不能穿过血脑屏障，但在接受治疗后，大脑的结构和功能会发生变化，相当数量的癌症幸存者会出现认知功能障碍。人们正在更好地了解CiCi发生的方式，但其中涉及的机制仍未解决。解释CiCi的假设不胜枚举。FDA批准的癌症化疗药物中，超过50%与活性氧物种(ROS)有关，ROS导致氧化应激，激活无数途径，以及正常大脑功能所需的抑制途径。氧化应激触发不同蛋白质的激活，其中一种是肿瘤坏死因子-α(肿瘤坏死因子-α)。在接受各种化疗药物治疗后，这种促炎细胞因子与血脑屏障上的受体结合，并通过受体介导的内吞作用转移到实质。一旦进入大脑，肿瘤坏死因子α启动的通路可能最终导致神经元死亡，最终导致认知障碍。肿瘤坏死因子α激活c-jun氨基末端激酶(JNK)和JAK/STAT信号转导和转录激活子(JAK/STAT)通路可能与化疗后患者的记忆减退和高级执行功能丧失有关。化疗还会影响大脑的抗氧化能力，从而导致ROS的积累。这篇综述对这些主题进行了扩展，以提供对氧化应激和肿瘤坏死因子α交叉参与化疗所致认知障碍的可能机制的见解。
Chemotherapy induced cognitive impairment (CICI) has been observed in a large fraction of cancer survivors. Although many of the chemotherapeutic drugs do not cross the blood brain barrier, following treatment the structure and function of the brain is altered and cognitive dysfunction occurs in a significant number of cancer survivors. The means by which CICI occurs is becoming better understood, but there still remain unsolved questions of the mechanisms involved. The hypotheses to explain CICI are numerous. More than 50 percent of FDA-approved cancer chemotherapy agents are associated with reactive oxygen species (ROS) that lead to oxidative stress and activate a myriad of pathways as well as inhibit pathways necessary for proper brain function. Oxidative stress triggers the activation of different proteins, one in particular is tumor necrosis factor alpha (TNFα). Following treatment with various chemotherapy agents, this pro-inflammatory cytokine binds to its receptors at the blood-brain barrier and translocates to the parenchyma via receptor-mediated endocytosis. Once in brain, TNFα initiates pathways that may eventually lead to neuronal death and ultimately cognitive impairment. TNFα activation of the c-jun N-terminal kinases (JNK) and Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways may contribute to both memory decline and loss of higher executive functions reported in patients after chemotherapy treatment. Chemotherapy also affects the brain’s antioxidant capacity, allowing for accumulation of ROS. This review expands on these topics to provide insights into the possible mechanisms by which the intersection of oxidative stress and TNFα are involved in chemotherapy induced cognitive impairment.
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