靶向过氧化物酶体增殖物激活受体-α（PPAR-α）以减轻紫杉醇诱导的周围神经病。
Targeting Peroxisome Proliferator-Activated Receptor-α (PPAR- α) to reduce paclitaxel-induced peripheral neuropathy.
机构信息
Department of Pharmacology and Toxicology and Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, USA.
Department of Pharmacology and Toxicology and Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, USA.
出版信息
Brain Behav Immun. 2021 Mar;93:172-185. doi: 10.1016/j.bbi.2021.01.004. Epub 2021 Jan 9.
BACKGROUND AND PURPOSE
Paclitaxel, a widely used anti-cancer drug, is frequently associated with prolonged and severe peripheral neuropathies (PIPN), associated with neuroinflammation. Currently, PIPN effective treatments are lacking. Peroxisome Proliferator-Activated Receptor-α (PPAR-⍺) can modulate inflammatory responses. Thus, the use of PPAR-⍺ agonists, such as fibrates (fenofibrate and choline-fenofibrate), currently used in dyslipidemia treatment, could represent an interesting therapeutic approach in PIPN.
EXPERIMENTAL APPROACH
Our studies tested the efficacy of fenofibrate (150 mg/kg, daily, i.p.) and choline fenofibrate (60 mg/kg daily, p.o.) in reversing and preventing the development of PIPN (paclitaxel: 8 mg/kg, i.p., every other day for 4 days) in male and female C57BL/6J mice. Mechanical and cold hypersensitivity, conditioned place preference, sensory nerve action potential (SNAP), as well as the expression of PPAR-⍺, TNF-⍺, IL-1β and IL-6 mRNA were evaluated.
KEY RESULTS
While fenofibrate treatment partially reversed and prevented the development of mechanical hypersensitivity, this was completely reversed and prevented by choline-fenofibrate. Both fibrates were able to completely reverse and prevent cold hypersensitivity induced by paclitaxel. The reduction of SNAP amplitude induced by paclitaxel was also reversed by both fenofibrate and choline-fenofibrate. Our results indicate that suppression of paclitaxel-induced hypersensitivity by fibrates involves the regulation of PPAR-⍺ expression and decrease neuroinflammation in DRG. Finally, the co-treatment of Paclitaxel and fenofibric acid (fibrates active metabolite) was tested on different cancer cell lines, no decrease in the antitumoral effect of paclitaxel was observed.
CONCLUSIONS AND IMPLICATIONS
Taken together, our results show for the first time the therapeutic potential (prevention and reversal) of fibrates in PIPN and opens to a potential pharmacological repurposing of these drugs.
背景与目的
紫杉醇是一种广泛应用的抗癌药物，常引起严重且持久的周围神经病变（PIPN），与神经炎症有关。目前，缺乏有效的 PIPN 治疗方法。过氧化物酶体增殖物激活受体-α（PPAR-α）可以调节炎症反应。因此，使用 PPAR-α 激动剂，如目前用于治疗血脂异常的贝特类药物（非诺贝特和胆碱非诺贝特），可能是 PIPN 的一种有前途的治疗方法。
实验方法
我们的研究测试了非诺贝特（150mg/kg，每天腹腔注射）和胆碱非诺贝特（60mg/kg，每天口服）在逆转和预防紫杉醇（8mg/kg，每隔一天腹腔注射一次，共 4 天）诱导的雄性和雌性 C57BL/6J 小鼠 PIPN 发展中的疗效。评估了机械和冷感觉过敏、条件性位置偏好、感觉神经动作电位（SNAP）以及 PPAR-α、TNF-α、IL-1β和 IL-6 mRNA 的表达。
主要结果
虽然非诺贝特治疗部分逆转和预防了机械性感觉过敏，但胆碱非诺贝特完全逆转和预防了这种过敏。两种贝特类药物均能完全逆转和预防紫杉醇引起的冷感觉过敏。紫杉醇引起的 SNAP 幅度降低也被非诺贝特和胆碱非诺贝特逆转。我们的结果表明，贝特类药物抑制紫杉醇诱导的过敏反应涉及 PPAR-α 表达的调节和 DRG 中神经炎症的减少。最后，测试了紫杉醇与非诺贝特酸（贝特类药物的活性代谢物）的联合治疗在不同癌细胞系中的作用，未观察到紫杉醇的抗肿瘤作用降低。
结论和意义
综上所述，我们的研究结果首次显示了贝特类药物在 PIPN 中的治疗潜力（预防和逆转），并为这些药物的潜在药理学再利用开辟了道路。
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