探讨NRF2过表达神经外泌体对顺铂引起的神经毒性保护作用的潜力及机制：NRF2/ARE通路的作用

神经毒性表现为有害化学物质（如重金属、药物）在神经组织中的积累，导致神经元死亡。铂类抗癌药因其抗肿瘤作用广泛使用，但也伴随多种毒性反应，包括神经毒性。核因子-红细胞相关因子2（NRF2）在抗氧化应激和维持细胞稳态中起关键作用。本研究系统探讨了由NRF2基因过表达神经前体细胞（NEVs）衍生的外泌体对顺铂诱导神经毒性的保护作用。首先分离并表征神经前体细胞的外泌体。顺铂在成熟的去分裂神经元中的毒性剂量为75 μM，正控制剂为诱导NRF2/ARE通路的1.25 μM叔丁基对苯醌（t-BHQ）。采用PCR和蛋白检测等功能和分子分析方法研究外泌体（EVs）的作用。结果显示，NEVs以剂量依赖方式保护去分裂神经元免受顺铂毒性作用。当预先给予1×10^8粒子/毫升的NEVs时，细胞和线粒体的抗氧化及解毒基因与蛋白表达水平保持在接近对照水平。此外，NEVs显著降低细胞和线粒体ROS水平，保持线粒体膜电位。NEV处理的细胞中，过氧化氢酶和超氧化物歧化酶（SOD）水平升高。该研究为基于NRF2的顺铂神经毒性保护提供了新证据，揭示了EVs与NRF2/ARE通路抑制神经应激的关系，有助于理解神经保护反应及开发基因工程EV治疗方案，用于周围神经病或其他神经退行性疾病。这是首个探讨NRF2过表达神经EV对顺铂神经毒性中和能力的研究。

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 75 µM in mature, post-mitotic neurons. 1.25 µM 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.