Targeting Peroxisome Proliferator-Activated Receptor-α (PPAR- α) to reduce paclitaxel-induced peripheral neuropathy.
Targeting Peroxisome Proliferator-Activated Receptor-α (PPAR- α) to reduce paclitaxel-induced peripheral neuropathy.
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靶向过氧化物酶体增殖物激活受体-α(PPAR-α)减轻紫杉醇诱导的周围神经病变。
DOI：
10.1016/j.bbi.2021.01.004
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Damaj MI
中科院分区：
文献类型：
--
作者：
Caillaud M;Patel NH;White A;Wood M;Contreras KM;Toma W;Alkhlaif Y;Roberts JL;Tran TH;Jackson AB;Poklis J;Gewirtz DA;Damaj MI
紫杉醇是一种广泛应用的抗癌药物，常引发与神经炎症相关的持续性严重周围神经病变（PIPN）。目前，针对PIPN缺乏有效的治疗方法。过氧化物酶体增殖物激活受体-α（PPAR-α）能够调节炎症反应。因此，使用目前用于治疗血脂异常的PPAR-α激动剂，如贝特类药物（非诺贝特和胆碱非诺贝特），可能是治疗PIPN的一种有前景的方法。
我们的研究在雄性和雌性C57BL/6J小鼠中，测试了非诺贝特（150毫克/千克，每日，腹腔注射）和胆碱非诺贝特（60毫克/千克，每日，口服）在逆转和预防PIPN（紫杉醇：8毫克/千克，腹腔注射，每两天一次，共4天）发展方面的功效。评估了机械性和冷超敏反应、条件性位置偏爱、感觉神经动作电位（SNAP），以及PPAR-α、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）mRNA的表达情况。
虽然非诺贝特治疗能部分逆转和预防机械性超敏反应的发展，但胆碱非诺贝特能完全逆转和预防。两种贝特类药物都能完全逆转和预防紫杉醇诱导的冷超敏反应。紫杉醇诱导的SNAP振幅降低也能被非诺贝特和胆碱非诺贝特逆转。我们的研究结果表明，贝特类药物对紫杉醇诱导的超敏反应的抑制作用，涉及对背根神经节（DRG）中PPAR-α表达的调节以及神经炎症的减轻。最后，在不同癌细胞系上测试了紫杉醇与非诺贝特酸（贝特类药物的活性代谢产物）的联合治疗，未观察到紫杉醇抗肿瘤效果的降低。
综上所述，我们的研究结果首次揭示了贝特类药物在PIPN中的治疗潜力（预防和逆转），为这些药物潜在的重新定位用于其他药理用途开辟了道路。
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-α) can modulate inflammatory responses. Thus, the use of PPAR-α agonists, such as fibrates (fenofibrate and choline-fenofibrate), currently used in dyslipidemia treatment, could represent an interesting therapeutic approach in PIPN. Our studies tested the efficacy of fenofibrate (150mg/kg, daily, i.p.) and choline fenofibrate (60mg/kg daily, p.o.) in reversing and preventing the development of PIPN (paclitaxel: 8mg/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-α, TNF-α, IL-1β and IL-6 mRNA were evaluated. 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-α 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. 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.
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影响因子：
4.4
作者：
Othman, Alaa;Benghozi, Renee;Hornemann, Thorsten
通讯作者：
Hornemann, Thorsten
DOI：
10.1523/jneurosci.0130-12.2012
发表时间：
2012-09-12
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Khasabova IA;Xiong Y;Coicou LG;Piomelli D;Seybold V
通讯作者：
Seybold V
影响因子：
4.7
作者：
Caillaud, Martial;Chantemargue, Benjamin;Billet, Fabrice
通讯作者：
Billet, Fabrice
影响因子：
2.5
作者：
通讯作者：
--
影响因子：
5
作者：
Burgos, Elisa;Gomez-Nicola, Diego;Goicoechea, Carlos
通讯作者：
Goicoechea, Carlos