Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Bâtiment 3 de la Faculté de Médecine, Université de Strasbourg, 11 rue Humann, 67000, Strasbourg, France.
Neurotox Res. 2020 Jun;38(1):145-162. doi: 10.1007/s12640-020-00176-2. Epub 2020 Feb 27.
Neoadjuvant chemotherapy is beneficial against breast cancer, but its toxicity causes painful chemotherapy-induced neuropathy which decreases seriously patients' quality of life. Development of effective therapy is crucial because current treatments are unsatisfactory. While animal models have previously been produced to test therapeutics against chemotherapy-induced neuropathy, neuropathic pain evoked by the frequently used neoadjuvant-chemotherapy involving sequentially epirubicin and docetaxel has never been modeled. Duloxetine, a serotonin/noradrenalin-reuptake inhibitor, is recommended against chemotherapy-induced neuropathy, but duloxetine exhibits controversial and adverse effects requiring its discontinuation. Here, we firstly produced and characterized a rat model for epirubicin-docetaxel induced painful neuropathy by using behavioral methods including the von Frey filament and the acetone tests that were combined with electrophysiological assessment of peripheral nerve functions and immunohistological analyzes. Using this model, we investigated the possibility to improve duloxetine efficacy and safety by combining its low doses (2 mg/kg/2 days) with the potent neuroprotector allopregnanolone (4 mg/kg/2 days). This concomitant therapy was more effective than separate duloxetine or allopregnanolone treatment to prevent epirubicin-docetaxel induced cold allodynia, mechanical allodynia/hyperalgesia, peripheral nerve functional/electrophysiological, and histological alterations. Interestingly, duloxetine-allopregnanolone concomitant treatment (but not duloxetine) also prevented epirubicin-docetaxel induced Schwann cell dedifferentiation and related macrophage (CD11b/c-positive cells) infiltration in sciatic nerves. Altogether, our results suggest that duloxetine and allopregnanolone concomitant treatment may represent a promising therapeutic option to counteract efficiently painful neuropathy or epirubicin-docetaxel evoked peripheral nerve tissue damages and dysfunctions.
新辅助化疗对乳腺癌有益，但它的毒性会导致疼痛的化疗引起的周围神经病变，严重降低患者的生活质量。开发有效的治疗方法至关重要，因为目前的治疗方法并不令人满意。虽然以前已经产生了动物模型来测试针对化疗引起的周围神经病变的治疗方法，但从未对涉及顺铂和多西紫杉醇的常用新辅助化疗引起的神经性疼痛进行建模。度洛西汀是一种 5-羟色胺/去甲肾上腺素再摄取抑制剂，被推荐用于治疗化疗引起的周围神经病变，但度洛西汀表现出有争议的和不良的作用，需要停药。在这里，我们首次通过使用行为方法（包括 von Frey 细丝和丙酮测试），结合周围神经功能的电生理评估和免疫组织化学分析，产生并表征了顺铂-多西紫杉醇诱导的痛性周围神经病变大鼠模型。使用该模型，我们研究了通过将其低剂量（2mg/kg/2 天）与有效的神经保护剂孕烷醇酮（4mg/kg/2 天）联合使用来提高度洛西汀疗效和安全性的可能性。这种联合治疗比单独使用度洛西汀或孕烷醇酮更有效地预防顺铂-多西紫杉醇引起的冷感觉过敏、机械性感觉过敏/痛觉过敏、周围神经功能/电生理学和组织学改变。有趣的是，度洛西汀-孕烷醇酮联合治疗（而不是度洛西汀）也预防了顺铂-多西紫杉醇引起的施万细胞去分化和相关巨噬细胞（CD11b/c 阳性细胞）在坐骨神经中的浸润。总之，我们的结果表明，度洛西汀和孕烷醇酮联合治疗可能是一种很有前途的治疗选择，可以有效地对抗疼痛性周围神经病变或顺铂-多西紫杉醇引起的周围神经组织损伤和功能障碍。
