Neurotoxic mechanisms of paclitaxel are local to the distal axon and independent of transport defects.
Neurotoxic mechanisms of paclitaxel are local to the distal axon and independent of transport defects.
复制标题
紫杉醇的神经毒性机制是远端轴突局部的，独立于运输缺陷。
DOI：
10.1016/j.expneurol.2016.11.015
复制
发表时间：
2017-03
影响因子：
5.3
通讯作者：
Schwarz TL
中科院分区：
文献类型：
--
作者：
Gornstein EL;Schwarz TL
化疗引起的周围神经病变（CIPN）是紫杉醇和其他化疗药物的剂量限制性副作用。紫杉醇结合并稳定微管，但紫杉醇神经毒性作用的细胞机制尚不清楚。因此，我们使用成年小鼠背根神经节神经元（患者中受影响的细胞类型）的原代培养来检验解释紫杉醇神经毒性的主要假设。我们解决了微管超稳定的作用及其下游效应。紫杉醇在10-50 nM剂量下给药1-3天，诱导轴突尖端的回缩球，阻止轴突生长，但不引发轴突断裂或细胞死亡。通过将结构不同的微管稳定化合物的毒性作用和微管稳定活性相关联，我们证实微管超稳定，而不是脱靶效应，可能是紫杉醇神经毒性的主要原因。我们检查了微管超稳定的潜在下游后果，发现微管蛋白翻译后修饰水平的变化，尽管在紫杉醇暴露后存在，但与我们在培养中观察到的紫杉醇神经毒性无关。此外，轴突运输缺陷并未被认为是紫杉醇对背根神经节神经元毒性作用的早期致病机制。我们利用微流控室选择性地用紫杉醇处理轴突不同部位，发现远端轴突对紫杉醇的影响主要是脆弱的，这表明紫杉醇直接作用于远端轴突诱导退行性作用。总之，我们的研究结果指出，微管超稳定在轴突远端大部分的局部作用是紫杉醇神经毒性的早期介质。由于感觉神经元具有独特且持续的远端生长需求，以便在表皮翻转时重新支配神经，我们提出紫杉醇阻止其生长的能力说明了感觉神经元对紫杉醇神经毒性的选择性脆弱性。
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of paclitaxel and other chemotherapeutic agents. Paclitaxel binds and stabilizes microtubules, but the cellular mechanisms that underlie paclitaxel’s neurotoxic effects are not well understood. We therefore used primary cultures of adult murine dorsal root ganglion neurons, the cell type affected in patients, to examine leading hypotheses to explain paclitaxel neurotoxicity. We address the role of microtubule hyperstabilization and its downstream effects. Paclitaxel administered at 10–50 nM for 1–3 days induced retraction bulbs at the tips of axons and arrested axon growth without triggering axon fragmentation or cell death. By correlating the toxic effects and microtubule stabilizing activity of structurally different microtubule stabilizing compounds, we confirmed that microtubule hyperstabilization, rather than an off-target effect, is the likely primary cause of paclitaxel neurotoxicity. We examined potential downstream consequences of microtubule hyperstabilization and found that changes in levels of tubulin posttranslational modifications, although present after paclitaxel exposure, are not implicated in the paclitaxel neurotoxicity we observed in the cultures. Additionally, defects in axonal transport were not implicated as an early, causative mechanism of paclitaxel’s toxic effects on dorsal root ganglion neurons. By using microfluidic chambers to selectively treat different parts of the axon with paclitaxel, we found that the distal axon was primarily vulnerable to paclitaxel, indicating that paclitaxel acts directly on the distal axon to induce degenerative effects. Together, our findings point to local effects of microtubule hyperstabilization on the distal-most portion of the axon as an early mediator of paclitaxel neurotoxicity. Because sensory neurons have a unique and ongoing requirement for distal growth in order to reinnervate the epidermis as it turns over, we propose that the ability of paclitaxel to arrest their growth accounts for the selective vulnerability of sensory neurons to paclitaxel neurotoxicity.
登录
查看更多内容
影响因子：
4.2
作者：
Das, Viswanath;Sim, Dalice A.;Miller, John H.
通讯作者：
Miller, John H.
影响因子：
5.3
作者：
Bober, Brian G.;Gutierrez, Edgar;Shah, Sameer B.
通讯作者：
Shah, Sameer B.
DOI：
10.1111/j.1460-9568.2011.07652.x
发表时间：
2011-05
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Bennett GJ;Liu GK;Xiao WH;Jin HW;Siau C
通讯作者：
Siau C
影响因子：
3
作者：
Boyette-Davis, Jessica A.;Cata, Juan P.;Driver, Larry C.;Novy, Diane M.;Bruel, Brian M.;Mooring, Deidre L.;Wendelschafer-Crabb, Gwen;Kennedy, William R.;Dougherty, Patrick M.
通讯作者：
Dougherty, Patrick M.
影响因子：
7.4
作者：
Flatters, SJL;Bennett, GJ
通讯作者：
Bennett, GJ