Bortezomib-induced painful peripheral neuropathy: an electrophysiological, behavioral, morphological and mechanistic study in the mouse.
Bortezomib-induced painful peripheral neuropathy: an electrophysiological, behavioral, morphological and mechanistic study in the mouse.
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DOI：
10.1371/journal.pone.0072995
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dorsey SG
中科院分区：
文献类型：
--
作者：
Carozzi VA;Renn CL;Bardini M;Fazio G;Chiorazzi A;Meregalli C;Oggioni N;Shanks K;Quartu M;Serra MP;Sala B;Cavaletti G;Dorsey SG
硼替佐米是第一个具有显著抗肿瘤活性的蛋白酶体抑制剂，用于治疗复发性/难治性多发性骨髓瘤以及其他血液学和实体肿瘤。周围神经系统并发症表现为感觉异常、烧灼感、感觉迟钝、麻木、感觉丧失、本体感觉和振动敏感性降低，是硼替佐米治疗的主要限制性副作用。虽然硼替佐米引起的疼痛性周围神经病变在临床上易于诊断，并且有可靠的模型，但其病理生理学仍不清楚。在这项研究中，我们使用了充分表征的免疫活性和免疫功能低下的硼替佐米诱导的疼痛性周围神经病变小鼠模型。为了表征药物诱导的周围神经系统病理变化，我们研究了脊髓神经元功能在神经性疼痛发展中的参与，并研究了硼替佐米诱导的疼痛性周围神经病变中免疫反应的相关性。我们发现硼替佐米治疗引起脊髓、背根、背根神经节（DRG）和周围神经的形态学变化。在周围神经纤维中也观察到Aδ和C纤维的神经生理异常和特异性功能改变。小鼠出现机械性痛觉超敏和脊髓背角宽动态范围神经元功能异常。硼替佐米诱导大多数DRG中神经元应激标记物激活转录因子-3的表达增加。此外，用硼替佐米治疗的免疫缺陷动物出现疼痛性周围神经病变，其特征与在免疫活性小鼠中观察到的相同。总之，本研究扩展了硼替佐米给药对神经系统损伤部位的认识。此外，周围神经纤维亚群的选择性功能脆弱性，以及脊髓背角的宽动态范围神经元的电活动的变化。最后，免疫应答不是硼替佐米在外周神经系统中诱导的形态和功能损伤发展的关键因素。
Bortezomib is the first proteasome inhibitor with significant antineoplastic activity for the treatment of relapsed/refractory multiple myeloma as well as other hematological and solid neoplasms. Peripheral neurological complications manifesting with paresthesias, burning sensations, dysesthesias, numbness, sensory loss, reduced proprioception and vibratory sensitivity are among the major limiting side effects associated with bortezomib therapy. Although bortezomib-induced painful peripheral neuropathy is clinically easy to diagnose and reliable models are available, its pathophysiology remains partly unclear. In this study we used well-characterized immune-competent and immune-compromised mouse models of bortezomib-induced painful peripheral neuropathy. To characterize the drug-induced pathological changes in the peripheral nervous system, we examined the involvement of spinal cord neuronal function in the development of neuropathic pain and investigated the relevance of the immune response in painful peripheral neuropathy induced by bortezomib. We found that bortezomib treatment induced morphological changes in the spinal cord, dorsal roots, dorsal root ganglia (DRG) and peripheral nerves. Neurophysiological abnormalities and specific functional alterations in Aδ and C fibers were also observed in peripheral nerve fibers. Mice developed mechanical allodynia and functional abnormalities of wide dynamic range neurons in the dorsal horn of spinal cord. Bortezomib induced increased expression of the neuronal stress marker activating transcription factor-3 in most DRG. Moreover, the immunodeficient animals treated with bortezomib developed a painful peripheral neuropathy with the same features observed in the immunocompetent mice. In conclusion, this study extends the knowledge of the sites of damage induced in the nervous system by bortezomib administration. Moreover, a selective functional vulnerability of peripheral nerve fiber subpopulations was found as well as a change in the electrical activity of wide dynamic range neurons of dorsal horn of spinal cord. Finally, the immune response is not a key factor in the development of morphological and functional damage induced by bortezomib in the peripheral nervous system.
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影响因子：
2.5
作者：
GUILBAUD, G;BENOIST, JM;GAUTRON, M
通讯作者：
GAUTRON, M
影响因子：
5.7
作者：
Jazirehi AR;Economou JS
通讯作者：
Economou JS
影响因子：
3.7
作者：
Carozzi, Valentina A.;Chiorazzi, Alessia;Cavaletti, Guido
通讯作者：
Cavaletti, Guido
DOI：
10.1186/2162-3619-1-20
发表时间：
2012-01-01
期刊：
EXPERIMENTAL HEMATOLGY & ONCOLOGY
影响因子：
--
作者：
Jeter, Ashley;Kang, Yubin
通讯作者：
Kang, Yubin
影响因子：
2.9
作者：
Cata, Juan P.;Weng, Han-Rong;Dougherty, Patrick M.
通讯作者：
Dougherty, Patrick M.