The challenge to identify sensitive safety biomarkers of peripheral neurotoxicity in the rat: A collaborative effort across industry and academia (IMI NeuroDeRisk project)

IF 4.8 3区医学 Q1 PHARMACOLOGY & PHARMACY

Toxicology Pub Date : 2024-11-17 DOI:10.1016/j.tox.2024.153998

Laura Micheli , David Balayssac , Jérôme Busserolles , Cristelle Dalbos , Laetitia Prival , Damien Richard , Mercedes Quintana , Lorenzo Di Cesare Mannelli , Alessandra Toti , Clara Ciampi , Carla Ghelardini , Katerina Vlasakova , Warren E. Glaab , Yang Hu , Irena Loryan , Olivier Perrault , Mohamed Slaoui , Kuno Wuersch , Eric Johnson , Wilfried Frieauff , Diethilde Theil

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引用次数: 0

Abstract

Peripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han). Clinical and/or functional endpoints (i.e., electronic Von Frey, Cold Plate, and Paw Pressure tests) and blood biomarkers (i.e., neurofilament light chain (NfL), neurofilament heavy chain (NF-H), microtubule-associated protein Tau (Tau), neuron specific enolase (NSE), vascular endothelial growth factor A (VEGFA), and glial fibrillary acidic protein (GFAP)) were assessed. Drug exposure and histopathological evaluations were conducted on selected nervous tissues. Oxaliplatin, cisplatin and paclitaxel treatment resulted in a significant decrease of nociceptive thresholds. Clinical signs suggestive of PNS toxicity were observed with NVS-1. NfL was consistently increased in the NVS-1 study and correlated with moderate microscopic findings in dorsal root ganglia (DRG). Only minimal microscopic findings were observed in oxaliplatin-treated animals, whereas no treatment-related microscopic findings were observed in animals treated with cisplatin and paclitaxel. For all compounds, exposure was confirmed in the PNS tissues. Clinical and functional changes were observed with all the compounds evaluated. NfL levels in plasma proved to be the most sensitive indicator of PNS toxicities, capturing moderate nervous degeneration in DRG. A combined approach that includes both functional assessments and biomarker measurements offers a more comprehensive evaluation than histopathological analysis alone when monitoring drug-induced neurotoxicity in rat models.

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确定大鼠外周神经毒性敏感安全生物标志物的挑战：跨行业和学术界的合作努力（IMI NeuroDeRisk 项目）。

非临床安全性研究中的外周神经系统（PNS）毒性评估具有挑战性，主要依赖于组织病理学评估。本研究旨在确定基于血液的生物标志物，以便在大鼠暴露于神经毒性化合物时检测其周围神经病变。本研究以雄性大鼠（Wistar Han）为对象，对三种抗癌剂（奥沙利铂、顺铂、紫杉醇）和一种发育化合物（NVS-1）进行了评估。评估了临床和/或功能终点（即电子 Von Frey、冷板和爪压测试）和血液生物标志物（即神经丝轻链（NfL）、神经丝重链（NF-H）、微管相关蛋白 Tau（Tau）、神经元特异性烯醇化酶（NSE）、血管内皮生长因子 A（VEGFA）和神经胶质纤维酸性蛋白（GFAP））。对选定的神经组织进行了药物暴露和组织病理学评估。奥沙利铂、顺铂和紫杉醇治疗导致痛觉阈值显著下降。在 NVS-1 中观察到了提示 PNS 毒性的临床症状。在 NVS-1 研究中，NfL 持续升高，并与背根神经节 (DRG) 中度显微镜检查结果相关。在接受奥沙利铂治疗的动物中仅观察到极少的显微镜下结果，而在接受顺铂和紫杉醇治疗的动物中未观察到与治疗相关的显微镜下结果。所有化合物的暴露均在 PNS 组织中得到证实。所有评估的化合物都观察到了临床和功能变化。血浆中的 NfL 水平被证明是 PNS 毒性最敏感的指标，可捕捉到 DRG 中度神经变性。在监测大鼠模型中药物诱导的神经毒性时，包括功能评估和生物标志物测量在内的综合方法比单独的组织病理学分析提供了更全面的评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology 医学-毒理学

CiteScore

7.80

自引率

4.40%

发文量

222

审稿时长

23 days

期刊介绍： Toxicology is an international, peer-reviewed journal that publishes only the highest quality original scientific research and critical reviews describing hypothesis-based investigations into mechanisms of toxicity associated with exposures to xenobiotic chemicals, particularly as it relates to human health. In this respect "mechanisms" is defined on both the macro (e.g. physiological, biological, kinetic, species, sex, etc.) and molecular (genomic, transcriptomic, metabolic, etc.) scale. Emphasis is placed on findings that identify novel hazards and that can be extrapolated to exposures and mechanisms that are relevant to estimating human risk. Toxicology also publishes brief communications, personal commentaries and opinion articles, as well as concise expert reviews on contemporary topics. All research and review articles published in Toxicology are subject to rigorous peer review. Authors are asked to contact the Editor-in-Chief prior to submitting review articles or commentaries for consideration for publication in Toxicology.