神经毒性的特点是重金属和药物等有害化学物质在神经组织中积累，导致随后的神经元死亡。在化学品中，铂基抗癌药物因其抗肿瘤作用而被频繁使用，但该药物也已知会引起广泛的毒性，例如神经毒性。核因子红细胞 2 相关因子 2 (NRF2) 对于对抗氧化应激和维持细胞稳态至关重要。本研究深入探讨了NRF2基因过表达神经祖细胞（NEV）来源的细胞外囊泡对顺铂诱导的神经毒性的保护作用。因此，分离并表征了源自神经祖细胞的细胞外囊泡。对于成熟的有丝分裂后神经元，顺铂的神经毒性剂量为 75μM。诱导NRF2/ARE途径的1.25μM叔丁基对苯二酚用作阳性对照。使用功能和分子检测（例如 PCR 和基于蛋白质的检测）研究了细胞外囊泡 (EV) 的影响。在这里，我们观察到 NEV 对顺铂的反应呈剂量依赖性保护有丝分裂后神经元细胞。该研究还检验了这种效应是否是通过限制 EV 生物发生而引起的。建立了预防性治疗的分子基础。预给药时，1×108 颗粒/mL 的 NEV 保持了与对照细胞水平相似的抗氧化和解毒基因和蛋白质表达水平。此外，NEV 降低了细胞和线粒体 ROS 水平并保留了线粒体膜电位。此外，与顺铂对照相比，NEV 处理的细胞中过氧化氢酶和 SOD 水平较高。基于 NRF2 对顺铂诱导的神经毒性的保护作用的发现可能为 EV 与通过 NRF2/ARE 途径抑制神经元应激之间的关系提供进一步的证据，从而增加对神经保护反应的理解以及基因工程 EV 治疗方案的开发周围神经病变或其他神经退行性疾病。这是文献中第一项研究 NRF2 过度表达的神经 EV 对顺铂诱导的神经毒性的中和效力。版权所有 © 2024。由 Elsevier B.V. 出版。

Neurotoxicity is characterized by the accumulation of harmful chemicals such as heavy metals and drugs in neural tissue, resulting in subsequent neuronal death. Among chemicals platinum-based cancer drugs are frequently used due to their antineoplastic effects, but this drug is also known to cause a wide range of toxicities, such as neurotoxicity. The nuclear-factor-erythroid 2-related factor-2 (NRF2) is crucial in combating oxidative stress and maintaining cellular homeostasis. This study thoroughly explores the protective effects of extracellular vesicles derived from NRF2 gene overexpressed neural progenitor cells (NEVs) on cisplatin-induced neurotoxicity. Therefore, extracellular vesicles derived from neural progenitor cells were isolated and characterized. The Cisplatin neurotoxicity dose was 75µM in mature, post-mitotic neurons. 1.25µM of tert-butyl hydroquinone that induces NRF2/ARE pathway was used as the positive control. The effects of extracellular vesicles (EVs) were investigated using functional and molecular assays such as PCR and protein-based assays. Here, we observed that NEVs dose-dependently protected post-mitotic neuron cells in response to cisplatin. The study also examined whether the effect was EV-induced by limiting EV biogenesis. The molecular basis of preventive treatment was established. When pre-administered, 1×108 particles/mL of NEVs maintained antioxidant and detoxifying gene and protein expression levels similar to control cell levels. Furthermore, NEVs reduced both cellular and mitochondrial ROS levels and preserved mitochondrial membrane potential. In addition, Catalase and SOD levels were found higher in NEV-treated cells compared to cisplatin control. The findings in NRF2-based protection of cisplatin-induced neurotoxicity may provide further evidence for the relationship between EVs and inhibition of neuronal stress through the NRF2/ARE pathway, increasing the understanding of neuroprotective responses and the development of gene-engineered EV therapy options for peripheral neuropathy or other neurodegenerative diseases. This is the first study in the literature to investigate the neutralizing potency of NRF2 overexpressed neural EVs against cisplatin-induced neurotoxicity.Copyright © 2024. Published by Elsevier B.V.