Paclitaxel-induced peripheral neurotoxicity (PIPN) is a potentially dose-limiting side effect in anticancer chemotherapy. Several animal models of PIPN exist, but their results are sometimes difficult to be translated into the clinical setting. We compared 2 widely used PIPN models characterized by marked differences in their methodologies. Female C57BL/6JOlaHsd mice were used, and they received only paclitaxel vehicle (n = 38) or paclitaxel via intravenous injection (n = 19, 70 mg/kg) once a week for 4 weeks (Study 1) or intraperitoneally (n = 19, 10 mg/kg) every 2 days for 7 times (Study 2). At the end of treatment and in the follow-up, mice underwent behavioral and neurophysiological assessments of PIPN. At the same time points, some mice were killed and dorsal root ganglia, skin, and sciatic and caudal nerve samples underwent pathological examination. Serum neurofilament light levels were also measured. The differences in the neurotoxicity parameters were analyzed using a nonparametric Mann-Whitney test, with significance level set at P < 0.05. Study 1 showed significant and consistent behavioral, neurophysiological, pathological, and serological changes induced by paclitaxel administration at the end of treatment, and most of these changes were still evident in the follow-up period. By contrast, study 2 evidenced only a transient small fiber neuropathy, associated with neuropathic pain. Our comparative study clearly distinguished a PIPN model recapitulating all the clinical features of the human condition and a model showing only small fiber neuropathy with neuropathic pain induced by paclitaxel.

中文翻译：

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紫杉醇诱导的周围神经毒性从小鼠到患者的转化：模型选择的重要性。

紫杉醇诱导的周围神经毒性（PIPN）是抗癌化疗中潜在的剂量限制副作用。存在多种 PIPN 动物模型，但它们的结果有时难以转化为临床环境。我们比较了两种广泛使用的 PIPN 模型，其特点是方法论上存在显着差异。使用雌性 C57BL/6JOlaHsd 小鼠，仅接受紫杉醇载体 (n = 38) 或静脉注射紫杉醇 (n = 19, 70 mg/kg)，每周一次，持续 4 周（研究 1）或腹膜内注射（n = 19） , 10 mg/kg) 每 2 天一次，共 7 次（研究 2）。在治疗结束和随访中，小鼠接受了 PIPN 的行为和神经生理学评估。同时处死部分小鼠，对背根神经节、皮肤、坐骨神经、尾神经样本进行病理检查。还测量了血清神经丝光水平。使用非参数Mann-Whitney 检验分析神经毒性参数的差异，显着性水平设定为P < 0.05。研究1显示在治疗结束时紫杉醇给药引起显着且一致的行为、神经生理学、病理学和血清学变化，并且大多数这些变化在随访期间仍然明显。相比之下，研究 2 仅证明存在与神经性疼痛相关的短暂性小纤维神经病。我们的比较研究清楚地区分了概括人类状况所有临床特征的 PIPN 模型和仅显示小纤维神经病变并伴有紫杉醇诱导的神经性疼痛的模型。