Duloxetine prevents bortezomib and paclitaxel large-fiber chemotherapy-induced peripheral neuropathy (LF-CIPN) in sprague dawley rats.
Duloxetine prevents bortezomib and paclitaxel large-fiber chemotherapy-induced peripheral neuropathy (LF-CIPN) in sprague dawley rats.
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DOI：
10.1177/17448069231185694
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发表时间：
2023-01
期刊：
影响因子：
3.3
通讯作者：
中科院分区：
文献类型：
--
作者：
化疗引起的周围神经病变（CIPN）是几类化疗药物的一种使人衰弱的、限制治疗的副作用。虽然对肿瘤患者的生活质量产生负面影响，但化疗诱导的大纤维（LF）神经病变是CIPN中了解最少的组成部分之一，目前还没有确定的治疗方法。初步临床观察表明，用于治疗与小纤维CIPN（SF-CIPN）相关疼痛的度洛沙汀可能对LF-CIPN有效。在本实验中，我们开发了一种LF-CIPN模型，并研究了度洛沙汀对两种神经毒性化疗药物诱导的LF-CIPN的影响：蛋白酶体抑制剂Bortezumab，多发性骨髓瘤的一线治疗;和抗微管紫杉烷Paclitaxine，用于治疗实体瘤。由于目前没有选择性研究LF-CIPN的模型，我们的第一个目标是在大鼠中建立临床前模型。LF-CIPN用电流感知阈值（CPT）测定进行评估，该测定使用选择性激活大纤维有髓鞘传入的高频（1000 Hz）电刺激方案。我们的第二个目的是使用该模型来检验度洛沙汀可以预防LF-CIPN的假设。我们报告硼替佐米和紫杉醇诱导CPT升高，与大纤维功能丧失相容，这可以被度洛沙汀预防。我们的研究结果支持临床观察，度洛沙汀可能是一种有效的治疗大纤维CIPN。我们还建议CPT可用作接受神经毒性化疗患者LF-CIPN的生物标志物。
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating, treatment-limiting, side-effect of several classes of chemotherapy drugs. While negatively impacting oncology patients’ quality of life, chemotherapy-induced large-fiber (LF) neuropathy is amongst the least well understood components of CIPN, and one for which there is currently no established therapy. Preliminary clinical observations have led to the suggestion that Duloxetine, which is used for the treatment of pain associated with small-fiber CIPN (SF-CIPN), may be effective against LF-CIPN. In the present experiments we developed a model of LF-CIPN and studied the effect of Duloxetine on LF-CIPN induced by two neurotoxic chemotherapy agents: the proteasome inhibitor, Bortezomib, a first-line treatment of multiple myeloma; and, the anti-microtubule taxane, Paclitaxel, used in the treatment of solid tumors. Since there are currently no models for selective the study of LF-CIPN, our first aim was to establish a pre-clinical model in the rat. LF-CIPN was evaluated with the Current Perception Threshold (CPT) assay, which uses a high frequency (1000 Hz) electrical stimulus protocol that selectively activates large-fiber myelinated afferents. Our second aim was to use this model to test the hypothesis that Duloxetine can prevent LF-CIPN. We report that Bortezomib and Paclitaxel induce elevation of CPT, compatible with loss of large-fiber function, which are prevented by Duloxetine. Our findings support the clinical observation that Duloxetine may be an effective treatment for the large-fiber CIPN. We also suggest that CPT could be used as a biomarker for LF-CIPN in patients receiving neurotoxic chemotherapy.
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