Warncke Urszula O, Toma Wisam, Meade Julie A, Park Abigail J, Thompson Danielle C, Caillaud Martial, Bigbee John W, Bryant Camron D, Damaj M Imad
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, United States.
Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, United States.
Front Pain Res (Lausanne). 2021 Jul 22;2:683168. doi: 10.3389/fpain.2021.683168. eCollection 2021.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose limiting, and long-lasting side effect of chemotherapy treatment. Unfortunately, no treatment has proven efficacious for this side effect. Rodent models play a crucial role in the discovery of new mechanisms underlying the initiation, progression, and recovery of CIPN and the potential discovery of new therapeutics. However, there is limited consistency in the dose, the sex, age, and genetic background of the animal used in these studies and the outcome measures used in evaluation of CIPN rely primarily on noxious and reflexive measures. The main objective of this study was to provide a comprehensive and systematic characterization of oxaliplatin-induced peripheral neuropathy in mice by using a battery of behavioral, sensory, electrophysiological, and morphometric measures in both sexes of the two widely used strains of mice, C57BL/6J and BALB/cJ. Mice received intraperitoneal injections of 3 or 30 mg/kg cumulative doses of oxaliplatin over the course of 2 weeks. Both doses induced long-term and time-dependent mechanical and cold hypersensitivity. Our results show that 30 mg/kg oxaliplatin reduced the locomotor activity in C57BL/6J mice, and C57BL/6J females showed anxiety-like behavior one-week post completion of treatment. In the same dose group, BALB/cJ males and females sustained a larger decrease in sucrose preference than either male or female C57BL/6J mice. Both strains failed to show significant changes in burrowing and nesting behaviors. Two clinically relevant assessments of changes to the peripheral nerve fibers, nerve conduction and intraepidermal nerve fiber density (IENFD) were evaluated. Only BALB/cJ females showed significant reduction in the nerve conduction amplitude 1 week after 30 mg/kg oxaliplatin regimen. Moreover, this dose of the chemo agent reduced the IENF density in both sexes and strains. Our findings suggest that mouse strain, sex, and assay type should be carefully considered when assessing the effects of oxaliplatin and potential therapeutic interventions.
化疗引起的周围神经病变（CIPN）是化疗治疗中常见的、剂量限制性的且持久的副作用。不幸的是，尚无治疗方法被证明对这种副作用有效。啮齿动物模型在发现CIPN发生、发展和恢复的新机制以及潜在新疗法的发现中起着关键作用。然而，这些研究中使用的动物的剂量、性别、年龄和遗传背景的一致性有限，并且用于评估CIPN的结果指标主要依赖于有害和反射性指标。本研究的主要目的是通过对两种广泛使用的小鼠品系C57BL/6J和BALB/cJ的雌雄小鼠进行一系列行为、感觉、电生理和形态测量，全面系统地表征奥沙利铂诱导的小鼠周围神经病变。小鼠在2周内接受腹腔注射累积剂量为3或30 mg/kg的奥沙利铂。两种剂量均诱导长期且时间依赖性的机械性和冷超敏反应。我们的结果表明，30 mg/kg奥沙利铂降低了C57BL/6J小鼠的运动活性，并且C57BL/6J雌性小鼠在治疗完成后一周表现出焦虑样行为。在相同剂量组中，BALB/cJ雄性和雌性小鼠的蔗糖偏好下降幅度大于C57BL/6J雄性或雌性小鼠。两个品系在掘洞和筑巢行为方面均未显示出显著变化。评估了外周神经纤维变化的两项临床相关评估指标，即神经传导和表皮内神经纤维密度（IENFD）。仅BALB/cJ雌性小鼠在30 mg/kg奥沙利铂给药方案后1周神经传导幅度显著降低。此外，该剂量的化疗药物降低了两性和两个品系的IENF密度。我们的研究结果表明，在评估奥沙利铂的作用和潜在治疗干预措施时，应仔细考虑小鼠品系、性别和检测类型。
