A Fenofibrate Diet Prevents Paclitaxel-Induced Peripheral Neuropathy in Mice.
A Fenofibrate Diet Prevents Paclitaxel-Induced Peripheral Neuropathy in Mice.
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DOI：
10.3390/cancers13010069
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发表时间：
2020-12-29
期刊：
影响因子：
5.2
通讯作者：
Damaj MI
中科院分区：
文献类型：
--
作者：
Caillaud M;Patel NH;Toma W;White A;Thompson D;Mann J;Tran TH;Roberts JL;Poklis JL;Bigbee JW;Fang X;Gewirtz DA;Damaj MI
紫杉醇是一种用于治疗肺癌、卵巢癌和乳腺癌等恶性肿瘤的药物，常产生严重的副作用，其中包括周围神经病变。这种神经病变表现为弥漫性或局部性疼痛，尤其是灼痛，以及对冷刺激和机械刺激的过度敏感。最近，非诺贝特，一种获美国食品药品监督管理局（FDA）批准用于治疗血脂异常的药物，已被证明能减轻其他类型周围神经病变的症状严重程度。在当前的研究中，我们测试了非诺贝特是否能逆转紫杉醇诱导的神经病变小鼠模型中的机械性和冷超敏反应，改善其运动能力，并缓解神经传导的降低。我们通过行为学、组织学和分子学评估表明，非诺贝特可预防紫杉醇诱导的神经病变的发展。综上所述，我们的研究支持非诺贝特在预防紫杉醇诱导的神经病变方面的治疗潜力，并提示该药物有可能在临床上重新用于这一目的。
背景：紫杉醇诱导的周围神经病变（PIPN）是这种用于治疗多种实体恶性肿瘤的化疗药物的主要不良反应。PIPN尤其会导致灼痛、冷痛觉过敏和机械性痛觉过敏。PIPN被认为是线粒体功能改变、神经元过度兴奋、神经纤维丢失、氧化应激以及背根神经节（DRG）和脊髓（SC）神经炎症的结果。因此，减轻神经炎症有可能缓解神经病变症状。过氧化物酶体增殖物激活受体-α（PPAR-α）是调节炎症反应的核受体，可被非选择性激动剂靶向作用，比如用于治疗血脂异常的非诺贝特。
方法：我们的研究测试了含非诺贝特（0.2%和0.4%）的饮食在预防PIPN发展方面的效果。对C57BL/6J小鼠（雄性和雌性）通过4次腹腔注射给予紫杉醇（8毫克/千克）。评估小鼠的机械性和冷超敏反应、转轮活动、感觉神经动作电位（SNAP）、坐骨神经组织学、表皮内神经纤维，以及DRG和SC中PPAR-α的表达和神经炎症情况。
结果：饮食中的非诺贝特部分预防了机械性超敏反应的发展，但完全预防了冷超敏反应以及紫杉醇诱导的转轮活动减少。非诺贝特还预防了紫杉醇诱导的SNAP振幅降低。我们的结果表明，非诺贝特对紫杉醇诱导疼痛的抑制作用涉及通过减轻神经炎症来调节PPAR-α的表达。最后，在卵巢癌和乳腺癌细胞系中，紫杉醇与非诺贝特的活性代谢产物（非诺贝特酸）联合使用，并不影响紫杉醇对肿瘤细胞生长或克隆形成能力的抑制作用。
结论：综上所述，我们的结果显示了非诺贝特在预防PIPN发展方面的治疗潜力。
Paclitaxel, a drug used in the treatment of malignancies such as lung, ovarian and breast cancer, often produces severe side effects, among which is peripheral neuropathy. This neuropathy involves diffuse or localized pain, notably burning pain, cold and mechanical hyperexcitability. Recently, fenofibrate, a Food and Drug Administration (FDA)-approved drug for the treatment of dyslipidemia, has been shown to reduce the severity of symptoms in other forms of peripheral neuropathy. In the current work, we tested whether fenofibrate could reverse mechanical and cold hypersensitivity and improve motivation and the reduction in nerve conduction in a mouse model of paclitaxel-induced neuropathy. Our behavioral, histological and molecular assessments indicate that fenofibrate prevents the development of paclitaxel-induced neuropathy. Taken together, our studies support the therapeutic potential of fenofibrate in the prevention of paclitaxel-induced neuropathy and suggest the possible repurposing of this drug for this purpose in the clinic. Background: Paclitaxel-induced peripheral neuropathy (PIPN) is a major adverse effect of this chemotherapeutic agent that is used in the treatment of a number of solid malignancies. PIPN leads notably to burning pain, cold and mechanical allodynia. PIPN is thought to be a consequence of alterations of mitochondrial function, hyperexcitability of neurons, nerve fiber loss, oxidative stress and neuroinflammation in dorsal root ganglia (DRG) and spinal cord (SC). Therefore, reducing neuroinflammation could potentially attenuate neuropathy symptoms. Peroxisome proliferator-activated receptor-α (PPAR-α) nuclear receptors that modulate inflammatory responses can be targeted by non-selective agonists, such as fenofibrate, which is used in the treatment of dyslipidemia. Methods: Our studies tested the efficacy of a fenofibrate diet (0.2% and 0.4%) in preventing the development of PIPN. Paclitaxel (8 mg/kg) was administered via 4 intraperitoneal (i.p.) injections in C57BL/6J mice (both male and female). Mechanical and cold hypersensitivity, wheel running activity, sensory nerve action potential (SNAP), sciatic nerve histology, intra-epidermal fibers, as well as the expression of PPAR-α and neuroinflammation were evaluated in DRG and SC. Results: Fenofibrate in the diet partially prevented the development of mechanical hypersensitivity but completely prevented cold hypersensitivity and the decrease in wheel running activity induced by paclitaxel. The reduction in SNAP amplitude induced by paclitaxel was also prevented by fenofibrate. Our results indicate that suppression of paclitaxel-induced pain by fenofibrate involves the regulation of PPAR-α expression through reduction in neuroinflammation. Finally, co-administration of paclitaxel and the active metabolite of fenofibrate (fenofibric acid) did not interfere with the suppression of tumor cell growth or clonogenicity by paclitaxel in ovarian and breast cancer cell lines. Conclusions: Taken together, our results show the therapeutic potential of fenofibrate in the prevention of PIPN development.