Bortezomib-induced painful neuropathy in rats: A behavioral, neurophysiological and pathological study in rats
Bortezomib-induced painful neuropathy in rats: A behavioral, neurophysiological and pathological study in rats
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DOI：
10.1016/j.ejpain.2009.07.001
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发表时间：
2010-04-01
影响因子：
3.6
通讯作者：
Cavaletti, Guido
中科院分区：
文献类型：
--
作者：
Meregalli, Cristina;Canta, Annalisa;Cavaletti, Guido
硼替佐米是一种蛋白酶体抑制剂，对许多肿瘤（主要是多发性骨髓瘤）显示出较强的抗肿瘤活性。硼替佐米引起的神经病理性疼痛是临床上该药的主要副作用和剂量限制因素。为了获得临床前模型以再现硼替佐米治疗患者的特征性疼痛症状，我们开发了硼替佐米诱导的伤害性感觉神经病的动物模型。在本研究中，将硼替佐米（0.15或0.20 mg/kg）给予Wistar大鼠，每周三次，持续8周，随后是4周的随访期。在给药期结束时，与对照组相比，给药组中观察到体重增量显著降低，并评价了血液学和组织病理学参数。治疗期后，两种剂量的硼替佐米均引起神经传导速度严重降低，并表现出药物的剂量累积效应。感觉行为评估显示机械异常性疼痛的发生，而对热感知没有影响。在治疗8周结束时和随访期结束时收集坐骨神经和背根神经节（DRG）。病理学检查显示治疗动物神经中无髓纤维的剂量依赖性轴突病。该动物模型对研究硼替佐米的神经毒性和疼痛发生机制具有重要意义。(C)2009年，国际疼痛分会研究协会欧洲联合会。由爱思唯尔有限公司出版。保留所有权利。
Bortezomib is a proteasome inhibitor showing strong antitumor activity against many tumors, primarily multiple myeloma. Bortezomib-induced neuropathic pain is the main side effect and the dose-limiting factor of the drug in clinical practice. In order to obtain a pre-clinical model to reproduce the characteristic pain symptoms in bortezomib-treated patients, we developed an animal model of bortezomib-induced nociceptive sensory neuropathy. In this study, bortezomib (0.15 or 0.20 mg/kg) was administered to Wistar rats three times/week for 8 weeks, followed by a 4 week follow-up period. At the end of the treatment period a significant decrease in weight gain was observed in the treated groups vs. controls, and hematological and histopathological parameters were evaluated. After the treatment period, both doses of bortezomib induced a severe reduction in nerve conduction velocity and demonstrated a dose-cumulative effect of the drug. The sensory behavioral assessment showed the onset of mechanical allodynia, while no effect on thermal perception was observed.Sciatic nerves and dorsal root ganglia (DRG) were collected at the end of the 8-week treatment and at the end of the follow-up period. The pathological examination revealed a dose-dependent axonopathy of the unmyelinated fibers in nerves of treated animals. No pathological alteration in most of DRG satellite cells and neurons was observed.Therefore, this animal model may be useful for studying the neurotoxicity and pain onset mechanisms related to bortezomib treatment. (C) 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.