Background

Doxorubicin (DOX)-induced neurotoxicity is widely reported in previous studies. Oxidative stress has been validated as a critical event involved in DOX-induced neurotoxicity. As a selective autophagy adaptor protein, p62 is reported to regulate Keap1-Nrf2-ARE antioxidant pathway in response to oxidative stress. Curcumin (CUR) relieves depressive-like state through the mitigation of oxidative stress and the activation of Nrf2-ARE signaling pathway. However, the exact mechanism of CUR in alleviating DOX-induced neurotoxicity is still unknown.

Materials and methods

The rats were randomly divided into three groups: control group, DOX group, and DOX + CUR group. At the end of 3 weeks, the behavior tests as sucrose preference test (SPT), forced swimming test (FST), and novelty-suppressed feeding test (NSFT) were performed to assess anxiety- and depression-like behaviors. The rats were sacrificed after behavior tests, and the brain tissues were collected for biochemical analysis.

Results

It was observed that the administration of CUR could effectively reverse DOX-induced depressive-like behaviors. The exposure of DOX activated autophagy and increased oxidative stress levels, and the administration of CUR could significantly inhibit DOX-induced autophagy and suppress oxidative stress. More importantly, we also found that Keap1-Nrf2-ARE signaling pathway was involved in DOX-induced neurotoxicity and oxidative stress regulated by autophagy.

Conclusion

Our study demonstrated that CUR could effectively reverse DOX-induced neurotoxicity through suppressing autophagy and mitigating oxidative stress and endoplasmic reticulum (ER) stress.

中文翻译：

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姜黄素通过调节 Keap1-Nrf2-ARE 和自噬信号通路防止阿霉素诱导的氧化应激

背景

阿霉素 (DOX) 诱导的神经毒性在以前的研究中被广泛报道。氧化应激已被验证为涉及 DOX 诱导的神经毒性的关键事件。作为一种选择性自噬衔接蛋白，据报道 p62 可调节 Keap1-Nrf2-ARE 抗氧化途径以应对氧化应激。姜黄素 (CUR) 通过减轻氧化应激和激活 Nrf2-ARE 信号通路来缓解抑郁样状态。然而，CUR 减轻 DOX 诱导的神经毒性的确切机制仍然未知。

材料和方法

大鼠随机分为三组：对照组、DOX组和DOX+CUR组。在 3 周结束时，进行行为测试，如蔗糖偏好测试（SPT）、强迫游泳测试（FST）和新奇抑制喂养测试（NSFT），以评估焦虑和抑郁样行为。行为学测试后处死大鼠，取脑组织进行生化分析。

结果

据观察，施用 CUR 可以有效地逆转 DOX 诱导的抑郁样行为。DOX 的暴露激活自噬并增加氧化应激水平，CUR 的给药可显着抑制 DOX 诱导的自噬并抑制氧化应激。更重要的是，我们还发现 Keap1-Nrf2-ARE 信号通路参与了 DOX 诱导的神经毒性和自噬调节的氧化应激。

结论

我们的研究表明，CUR 可以通过抑制自噬和减轻氧化应激和内质网 (ER) 应激来有效逆转 DOX 诱导的神经毒性。