Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation
Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation
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DOI：
10.1080/15376516.2019.1600086
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发表时间：
2019-06-14
影响因子：
3.2
通讯作者：
Suppiramaniam, Vishnu
中科院分区：
文献类型：
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作者：
Alhowail, Ahmad H.;Bloemer, Jenna;Suppiramaniam, Vishnu
化疗药物治疗后的患者通常会报告认知缺陷。含蒽环类药物的化疗方案与癌症幸存者的认知障碍和神经元连接性降低有关，阿霉素（Dox）是一种常用的蒽环类药物。尽管据报道阿霉素向中枢神经系统（CNS）的分布有限，但在联合使用某些药物时，大脑中会观察到相当高的阿霉素浓度。此外，在癌症中或对化疗产生的促炎细胞因子会降低血脑屏障（BBB）的完整性。因此，本研究的目的是评估阿霉素对海马神经元的急性神经毒性作用。在本研究中，我们利用海马细胞系（H19 - 7/IGF - IR）以及啮齿动物海马切片来评估阿霉素的急性神经毒性作用。海马切片用于测量长时程增强（LTP），蛋白质的表达通过免疫印迹法测定。还利用了线粒体复合物活性和脂质过氧化的细胞检测方法。我们观察到阿霉素处理的海马切片中LTP降低。此外，通过硫代巴比妥酸反应物含量测量发现脂质过氧化增加，表明存在氧化应激。半胱天冬酶 - 3的表达增加，表明细胞死亡倾向增加。最后，调节LTP的信号分子包括细胞外信号调节激酶1/2（ERK1/2）、p38丝裂原活化蛋白激酶和Akt的磷酸化增加。这些数据表明，急性阿霉素暴露以剂量依赖的方式损害与海马神经传递相关的突触过程，诱导细胞凋亡，并增加脂质过氧化，从而导致神经毒性。
Cognitive deficits are commonly reported by patients following treatment with chemotherapeutic agents. Anthracycline-containing chemotherapy regimens are associated with cognitive impairment and reductions in neuronal connectivity in cancer survivors, and doxorubicin (Dox) is a commonly used anthracycline. Although it has been reported that Dox distribution to the central nervous system (CNS) is limited, considerable Dox concentrations are observed in the brain with co-administration of certain medications. Additionally, pro-inflammatory cytokines, which are overproduced in cancer or in response to chemotherapy, can reduce the integrity of the blood-brain barrier (BBB). Therefore, the aim of this study was to evaluate the acute neurotoxic effects of Dox on hippocampal neurons. In this study, we utilized a hippocampal cell line (H19-7/IGF-IR) along with rodent hippocampal slices to evaluate the acute neurotoxic effects of Dox. Hippocampal slices were used to measure long-term potentiation (LTP), and expression of proteins was determined by immunoblotting. Cellular assays for mitochondrial complex activity and lipid peroxidation were also utilized. We observed reduction in LTP in hippocampal slices with Dox. In addition, lipid peroxidation was increased as measured by thiobarbituric acid reactive substances content indicating oxidative stress. Caspase-3 expression was increased indicating an increased propensity for cell death. Finally, the phosphorylation of signaling molecules which modulate LTP including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, and Akt were increased. This data indicates that acute Dox exposure dose-dependently impairs synaptic processes associated with hippocampal neurotransmission, induces apoptosis, and increases lipid peroxidation leading to neurotoxicity.