Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
Experimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
Exp Neurol. 2020 Dec;334:113458. doi: 10.1016/j.expneurol.2020.113458. Epub 2020 Sep 2.
Chemotherapy-induced peripheral neurotoxicity represents one of the most relevant dose-limiting side effects that can affect cancer patients treated with the common antineoplastic agents. Since the severity of neurotoxicity often leads to dose reduction or early cessation of chemotherapy, the investigation of molecular mechanisms underlying chemotherapy-induced peripheral neurotoxicity is an urgent clinical need in order to better understand its physiopathology and find effective strategies for neuroprotection. Several in vivo preclinical models of chemotherapy-induced peripheral neurotoxicity have been developed but a great variability in mouse strain, dose, route of administration of the drug, treatment schedule and assessment of neurotoxicity is observed between the different published studies making difficult the comparison and interpretation of their results. In many of these studies only behavioural tests are used as outcome measures, while possible neurophysiological and neuropathological changes are not evaluated. In this study, focused on experimental oxaliplatin-induced peripheral neurotoxicity, we reproduced and compared four mouse models with very different drug dose (low or high dose-intensity) and treatment schedules (short or long-term treatment), selected from the literature. Using a multimodal assessment based on behavioural, neurophysiological and neuropathological methods, we evidenced remarkable differences in the results obtained in the selected animal models. This work suggests the importance of a multimodal approach including extensive pathological investigation to confirm the behavioural results.
化疗引起的周围神经毒性是最相关的剂量限制副作用之一，可影响接受常见抗肿瘤药物治疗的癌症患者。由于神经毒性的严重程度常常导致剂量减少或化疗提前终止，因此研究化疗引起的周围神经毒性的分子机制是一种迫切的临床需求，以便更好地了解其病理生理学，并找到有效的神经保护策略。已经开发了几种化疗引起的周围神经毒性的体内临床前模型，但在不同的已发表研究中，观察到小鼠品系、药物剂量、给药途径、治疗方案和神经毒性评估之间存在很大的差异，这使得比较和解释其结果变得困难。在这些研究中，许多仅使用行为测试作为结果测量，而没有评估可能的神经生理学和神经病理学变化。在这项针对实验性奥沙利铂诱导的周围神经毒性的研究中，我们复制并比较了文献中选择的四种具有非常不同药物剂量（低或高剂量强度）和治疗方案（短期或长期治疗）的小鼠模型。使用基于行为、神经生理学和神经病理学方法的多模态评估，我们证明了所选动物模型中获得的结果存在显著差异。这项工作表明，包括广泛的病理学研究在内的多模态方法对于确认行为结果非常重要。
