Group of Neuroplasticity and Regeneration, Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Exp Neurol. 2010 Jun;223(2):599-608. doi: 10.1016/j.expneurol.2010.02.006. Epub 2010 Feb 24.
Bortezomib, a proteasome inhibitor, is an antineoplastic drug to treat multiple myeloma and mantle cell lymphoma. Its most clinically significant adverse event is peripheral sensory neuropathy. Our objective was to characterize the neuropathy induced by bortezomib in a mouse model. Two groups were used; one group received vehicle solution and another bortezomib (1mg/kg/twice/week) for 6weeks (total dose as human schedule). Tests were performed during treatment and for 4weeks post dosing to evaluate electrophysiological, autonomic, pain sensibility and sensory-motor function changes. At the end of treatment and after washout, sciatic and tibial nerves, dorsal ganglia and intraepidermal innervation were analyzed. Bortezomib induced progressive significant decrease of sensory action potential amplitude, mild reduction of sensory velocities without effect in motor conductions. Moreover, it significantly increased pain threshold and sensory-motor impairment at 6weeks. According to these data, histopathological findings shown a mild reduction of myelinated (-10%; p=0.001) and unmyelinated fibers (-27%; p=0.04), mostly involving large and C fibers, with abnormal vesicular inclusion body in unmyelinated axons. Neurons were also involved as shown by immunohistochemical phenotypic switch. After washout, partial recovery was observed in functional, electrophysiological and histological analyses. These results suggest that axon and myelin changes might be secondary to an initial dysfunctional neuronopathy.
硼替佐米是一种蛋白酶体抑制剂，是一种用于治疗多发性骨髓瘤和套细胞淋巴瘤的抗肿瘤药物。其最具临床意义的不良事件是周围感觉神经病。我们的目的是在小鼠模型中描述硼替佐米引起的神经病。使用两组；一组接受载体溶液，另一组接受硼替佐米（1mg/kg/两次/周）治疗 6 周（总剂量为人类方案）。在治疗期间和给药后 4 周进行测试，以评估电生理、自主、疼痛敏感性和感觉运动功能变化。在治疗结束和洗脱后，分析坐骨神经和胫神经、背根神经节和表皮内神经支配。硼替佐米诱导感觉动作电位幅度进行性显著降低，感觉速度轻度降低，但对运动传导无影响。此外，它在 6 周时显著增加了疼痛阈值和感觉运动障碍。根据这些数据，组织病理学发现显示有髓纤维（-10%；p=0.001）和无髓纤维（-27%；p=0.04）轻度减少，主要涉及大纤维和 C 纤维，无髓轴突中存在异常囊泡包涵体。神经元也参与其中，如免疫组织化学表型转换所示。洗脱后，在功能、电生理和组织学分析中观察到部分恢复。这些结果表明，轴突和髓鞘变化可能继发于初始的神经元功能障碍。
