Center for Biomedical Engineering and Science, Department of Mechanical Engineering and Engineering Science, University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States.
ACS Chem Neurosci. 2024 Mar 20;15(6):1157-1168. doi: 10.1021/acschemneuro.3c00739. Epub 2024 Mar 6.
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.
植酸（PA）已被报道具有抗炎和抗氧化特性，这对于神经元疾病中的神经保护至关重要。这就提出了一个问题，即 PA 是否可以有效保护感觉神经元免受化疗引起的周围神经病（CIPN）的影响。周围神经病是化疗治疗的一种剂量限制副作用，其特征通常是手脚严重和异常疼痛，这是由于周围神经退化引起的。目前，除了对症治疗外，没有有效的治疗方法可以预防或治愈周围神经病变。在此，我们旨在证明 PA 对顺铂（CDDP）和奥沙利铂引起的神经退行性变的神经保护作用。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 PA 对神经元的保护作用和生存能力。进行了显微镜下的细胞表型研究。通过荧光探针二氯荧光素估计细胞内活性氧（ROS）。同样，通过荧光 MitoTracker Orange CMTMRos 评估线粒体膜电位（MMP）。同样，评估了有和没有 PA 时 CDDP 引起的线粒体定位超氧阴离子自由基。用 CDDP 培养原代 DRG 神经元会降低轴突长度和整体神经元存活率。然而，与 PA 共同处理表明，轴突完全受到保护，并在 45 天的测试期间显示出稳定性增加，这与单独用 PA 处理和对照样本相当。值得注意的是，PA 处理清除了主要由 CDDP 诱导的线粒体特异性超氧自由基和整体细胞内 ROS，同时恢复了 MMP。这些结果归因于 PA 在铂处理条件下的潜在神经保护作用。研究结果还表明，PA 与 CDDP 在体外卵巢癌模型中具有协同抗癌作用。这是首次系统地证明 PA 对 CDDP 诱导的 PN 的作用。本研究的总体结果表明，PA 可用于预防和治疗 CIPN。
