Phytic Acid Maintains Peripheral Neuron Integrity and Enhances Survivability against Platinum-Induced Degeneration via Reducing Reactive Oxygen Species and Enhancing Mitochondrial Membrane Potential
Phytic Acid Maintains Peripheral Neuron Integrity and Enhances Survivability against Platinum-Induced Degeneration via Reducing Reactive Oxygen Species and Enhancing Mitochondrial Membrane Potential
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DOI：
10.1021/acschemneuro.3c00739
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发表时间：
2024-03-06
影响因子：
5
通讯作者：
Yang，In Hong
中科院分区：
文献类型：
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作者：
Tiwari，Arjun Prasad;Albin，Bayne;Yang，In Hong
植酸（PA）具有抗炎和抗氧化特性，对神经元疾病的神经保护至关重要。这就提出了一个问题，PA是否可以有效地保护感觉神经元免受化疗诱导的周围神经病变（CIPN）。周围神经病变是化疗治疗的剂量限制性副作用，其特征通常是由周围神经变性引起的手部和足部的严重和异常疼痛。目前，除了对症治疗外，还没有有效的治疗方法可以预防或治愈周围神经病变。在此，我们的目的是证明PA对化疗药物顺铂（CDDP）和奥沙利铂诱导的神经变性的神经保护作用。本研究的进一步目的是提供PA介导的神经保护的拟议机制。通过测量背根神经节（DRG）神经元的轴突长度和细胞体计数来表征对CDDP的神经元保护和存活能力。在显微镜下进行细胞表型研究。用荧光探针二氯荧光素检测细胞内活性氧。同样，通过荧光MitoTracker橙子CMTMRos评估线粒体膜电位（MMP）。同样地，评估了在有和没有PA的情况下，CDDP响应的O2-本地化超氧阴离子自由基。原代DRG神经元与CDDP的培养减少了轴突长度和总体神经元存活。然而，与PA的共治疗表明，轴突完全保护，并显示出增加的稳定性高达45天的测试持续时间，这是与PA单独和对照处理的样品。值得注意的是，PA治疗清除了大部分由CDDP诱导的细胞内的超氧化物自由基和总的ROS，同时恢复MMP。这些结果归功于PA在铂治疗条件下的潜在神经保护作用。结果还表明，PA与顺铂在卵巢癌体外模型中具有协同抗癌作用。首次系统地证明了PA对CDDP诱导的PN的效力。本研究的总体结果表明PA在CIPN预防和治疗目的中的应用。
Phytic acid (PA) has been reported to possess anti-inflammatory and antioxidant properties that are critical for neuroprotection in neuronal disorders. This raises the question of whether PA can effectively protect sensory neurons against chemotherapy-induced peripheral neuropathy (CIPN). Peripheral neuropathy is a dose-limiting side effect of chemotherapy treatment often characterized by severe and abnormal pain in hands and feet resulting from peripheral nerve degeneration. Currently, there are no effective treatments available that can prevent or cure peripheral neuropathies other than symptomatic management. Herein, we aim to demonstrate the neuroprotective effects of PA against the neurodegeneration induced by the chemotherapeutics cisplatin (CDDP) and oxaliplatin. Further aims of this study are to provide the proposed mechanism of PA-mediated neuroprotection. The neuronal protection and survivability against CDDP were characterized by axon length measurements and cell body counting of the dorsal root ganglia (DRG) neurons. A cellular phenotype study was conducted microscopically. Intracellular reactive oxygen species (ROS) was estimated by fluorogenic probe dichlorofluorescein. Likewise, mitochondrial membrane potential (MMP) was assessed by fluorescent MitoTracker Orange CMTMRos. Similarly, the mitochondria-localized superoxide anion radical in response to CDDP with and without PA was evaluated. The culture of primary DRG neurons with CDDP reduced axon length and overall neuronal survival. However, cotreatment with PA demonstrated that axons were completely protected and showed increased stability up to the 45-day test duration, which is comparable to samples treated with PA alone and control. Notably, PA treatment scavenged the mitochondria-specific superoxide radicals and overall intracellular ROS that were largely induced by CDDP and simultaneously restored MMP. These results are credited to the underlying neuroprotection of PA in a platinum-treated condition. The results also exhibited that PA had a synergistic anticancer effect with CDDP in ovarian cancer in vitro models. For the first time, PA’s potency against CDDP-induced PN is demonstrated systematically. The overall findings of this study suggest the application of PA in CIPN prevention and therapeutic purposes.