Center for Biomedical Engineering and Science, Department of Mechanical Engineering and Engineering Science, University of North Carolina at Charlotte, Charlotte, NC 28223, United States.
Center for Biomedical Engineering and Science, Department of Mechanical Engineering and Engineering Science, University of North Carolina at Charlotte, Charlotte, NC 28223, United States.
Life Sci. 2023 Dec 1;334:122219. doi: 10.1016/j.lfs.2023.122219. Epub 2023 Oct 29.
Chemotherapy induced peripheral neuropathy (CIPN) is a common side effect seen in patients who have undergone most chemotherapy treatments to which there are currently no treatment methods. CIPN has been shown to cause axonal degeneration leading to Peripheral Neuropathy (PN), which can lead to major dosage reduction and may prevent further chemotherapy treatment due to oftentimes debilitating pain. Previously, we have determined the site-specific action of Paclitaxel (PTX), a microtubule targeting agent, as well as the neuroprotective effect of Fluocinolone Acetonide (FA) against Paclitaxel Induced Peripheral Neuropathy (PIPN).
Mitochondrial trafficking analysis was determined for all sample sets, wherein FA showed enhanced anterograde (axonal) mitochondrial trafficking leading to neuroprotective effects for all samples.
Using this system, we demonstrate that PTX, Monomethyl auristatin E (MMAE), and Vincristine (VCR), are toxic at clinically prescribed levels when treated focally to axons. However, Cisplatin (CDDP) was determined to have a higher toxicity when treated to cell bodies. Although having different targeting mechanisms, the administration of FA was determined to have a significant neuroprotective effect for against all chemotherapy drugs tested.
This study identifies key insights regarding site of action and neuroprotective strategies to further development as potential therapeutics against CIPN. FA was treated alongside each chemotherapy drug to identify the neuroprotective effect against CIPN, where FA was found to be neuroprotective for all drugs tested. This study found that treatment with FA led to an enhancement in the anterograde movement of mitochondria based on fluorescent imaging.
化疗引起的周围神经病（CIPN）是接受大多数化疗治疗的患者常见的副作用，目前尚无治疗方法。CIPN 已被证明会导致轴突变性，从而导致周围神经病（PN），这可能导致剂量大幅减少，并可能由于经常使人衰弱的疼痛而阻止进一步的化疗治疗。以前，我们已经确定了紫杉醇（PTX），一种微管靶向剂的特定部位作用，以及氟轻松醋酸酯（FA）对紫杉醇诱导的周围神经病（PIPN）的神经保护作用。
对所有样本集进行线粒体转运分析，其中 FA 显示增强的顺行（轴突）线粒体转运，从而对所有样本产生神经保护作用。
使用该系统，我们证明 PTX、单甲基奥瑞他汀 E（MMAE）和长春新碱（VCR）在临床上规定的水平下局部作用于轴突时是有毒的。然而，顺铂（CDDP）被确定在治疗细胞体时具有更高的毒性。尽管具有不同的靶向机制，但 FA 的给药被确定对所有测试的化疗药物具有显著的神经保护作用。
这项研究确定了有关作用部位和神经保护策略的关键见解，以进一步开发作为治疗 CIPN 的潜在疗法。FA 与每种化疗药物一起治疗，以确定对 CIPN 的神经保护作用，结果发现 FA 对所有测试药物均具有神经保护作用。这项研究发现，FA 的治疗导致基于荧光成像的线粒体顺行运动增强。
