Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat
Bortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat
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DOI：
10.1016/j.expneurol.2006.11.010
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发表时间：
2007-03-01
影响因子：
5.3
通讯作者：
De Coster, Roland
中科院分区：
文献类型：
--
作者：
Cavaletti, Guido;Gilardini, Alessandra;De Coster, Roland
硼替佐米是一种新的蛋白酶体抑制剂，具有高抗肿瘤活性，但也具有潜在的严重外周神经毒性。为了建立临床前模型并表征外周神经、背根神经节（DRG）和脊髓中诱导的变化，对Wistar大鼠给予硼替佐米（0.08、0.15、0.20、0.30 mg/kg/天，每周两次[2 q7 d]或三次[3q 7 d]，共4周）。在基线时、治疗期开始后第14、21和28天以及4周随访期期间，测定每只动物尾部的感觉神经传导速度（SNCV）。结果表明，在最大耐受剂量下，硼替佐米可使SNCV显著降低，并在随访期结束时完全恢复。坐骨神经检查和形态计量学测定显示，以雪旺细胞和髓鞘为主的轻度至中度病理改变，尽管也观察到轴突变性。在DRG中也观察到硼替佐米诱导的变化，表现为线粒体和内质网损伤导致的卫星细胞胞浆内空泡化，与坐骨神经雪旺细胞中观察到的变化非常相似。DRG神经元的胞质颜色深，胞质内有透明空泡，但这种现象很少出现。脊髓形态正常。该模型与硼替佐米治疗人类恶性肿瘤时诱导的神经病变相关，并且可能有助于增加我们对硼替佐米神经毒性机制的了解。(c)2006年爱思唯尔公司All rights reserved.
Bortezomib is a new proteasome inhibitor with a high antitumor activity, but also with a potentially severe peripheral neurotoxicity. To establish a preclinical model and to characterize the changes induced on the peripheral nerves, dorsal root ganglia (DRG) and spinal cord, bortezomib was administered to Wistar rats (0.08, 0.15, 0.20, 0.30 mg/kg/day twice [2q7d] or three times [3q7d] weekly for a total of 4 weeks). At baseline, on days 14, 21 and 28 after the beginning the treatment period and during a 4-week follow-up period sensory nerve conduction velocity (SNCV) was determined in the tail of each animal. Sciatic nerve, DRG and spinal cord specimens were processed for light and electron microscope observations and morphometry.At the maximum tolerated dose bortezomib induced a significant reduction in SNCV, with a complete recovery at the end of the follow-up period.Sciatic nerve examination and morphometric determinations demonstrated mild to moderate pathological changes, involving predominantly the Schwann cells and myelin, although axonal degeneration was also observed. Bortezomib-induced changes were also observed in DRG and they were represented by satellite cell intracytoplasmatic vactiolization due to mitochondrial and endoplasmic reticulum damage, closely resembling the changes observed in sciatic nerve Schwann cells. Only rarely did the cytoplasm of DRG neurons has a dark appearance and clear vacuoles occurring in the cytoplasm. Spinal cord was morphologically normal.This model is relevant to the neuropathy induced by bortezomib in the treatment of human malignancies and it could be useful in increasing our knowledge regarding the mechanisms underlying bortezomib neurotoxicity. (c) 2006 Elsevier Inc. All rights reserved.