Calpain inhibition protects against Taxol-induced sensory neuropathy
Calpain inhibition protects against Taxol-induced sensory neuropathy
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DOI：
10.1093/brain/awh078
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发表时间：
2004-03-01
期刊：
影响因子：
14.5
通讯作者：
Glass, JD
中科院分区：
文献类型：
--
作者：
Wang, MS;Davis, AA;Glass, JD
紫杉醇是一种高效的抗癌药物，其主要毒副作用是引起周围神经病变。神经病变的特征在于感觉轴突的变性，其可能严重到足以限制剂量。轴突变性涉及钙激活蛋白酶钙蛋白酶的激活，在这里，我们测试了用肽α-酮酰胺钙蛋白酶抑制剂AK 295全身抑制钙蛋白酶是否可以减少紫杉醇在啮齿动物模型中的临床和病理作用。在患有紫杉醇神经病的小鼠中，AK 295降低了感觉神经根轴突变性的程度，并改善了神经病的临床指标，包括行为和电生理功能。这些结果在3周和6周神经病变模型中一致。在体外，紫杉醇引起激活的钙蛋白酶和半胱天冬酶在PC 12细胞。AK 295抑制钙蛋白酶的激活，但不干扰紫杉醇对微管的抗有丝分裂作用，也不抑制半胱天冬酶介导的细胞死亡。这些数据暗示钙蛋白酶在Taxol神经病的发病机制中，并证明AK 295可以预防小鼠的轴突变性和临床神经病。此外，AK 295不干扰紫杉醇对微管和细胞死亡的主要抑制作用，表明全身性钙蛋白酶抑制可能是预防紫杉醇治疗患者神经病变的良好策略。
Taxol is a highly effective anticancer agent that causes peripheral neuropathy as its major toxic side effect. The neuropathy is characterized by degeneration of sensory axons that may be severe enough to be dose limiting. Axonal degeneration involves the activation of the calcium-activated proteases calpains, and here we tested whether systemic inhibition of calpains with the peptide alpha-ketoamide calpain inhibitor AK295 can reduce the clinical and pathological effects of Taxol in a rodent model of Taxol neuropathy. In mice with Taxol neuropathy, AK295 reduced the degree of axonal degeneration in sensory nerve roots, and improved clinical measures of neuropathy, including behavioural and electrophysiological function. These findings were consistent for both 3- and 6-week models of neuropathy. In vitro, Taxol caused activation of both calpains and caspases in PC12 cells. AK295 inhibited the activation of calpains but did not interfere with the antimitotic effects of Taxol on microtubules, nor did it inhibit caspase-mediated cell death. These data implicate calpains in the pathogenesis of Taxol neuropathy, and demonstrate that AK295 can prevent axonal degeneration and clinical neuropathy in mice. In addition, AK295 did not interfere with the primary antineoplastic effects of Taxol on microtubules and cell death, suggesting that systemic calpain inhibition may be a good strategy for preventing neuropathy in patients being treated with Taxol.