Targeting Peroxisome Proliferator-Activated Receptor- ? (PPAR- ? ) to reduce paclitaxel-induced peripheral neuropathy

被引：34

作者：

Caillaud, Martial ^{[1
,2
]}

Patel, Nipa H. ^{[1
,2
]}

White, Alyssa ^{[1
,2
]}

Wood, Mackinsey ^{[1
,2
]}

Contreras, Katherine M. ^{[1
,2
]}

Toma, Wisam ^{[1
,2
]}

Alkhlaif, Yasmin ^{[1
,2
]}

Roberts, Jane L. ^{[1
,2
]}

Tran, Tammy H. ^{[1
,2
]}

Jackson, Asti B. ^{[1
,2
]}

Poklis, Justin ^{[1
,2
]}

Gewirtz, David A. ^{[1
,2
]}

Damaj, M. Imad ^{[1
,2
]}

机构：

[1] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23284 USA

[2] Virginia Commonwealth Univ, Translat Res Initiat Pain & Neuropathy, Richmond, VA 23284 USA

来源：

BRAIN BEHAVIOR AND IMMUNITY | 2021年 / 93卷

关键词：

Fibrates; Chemotherapy; Peripheral neuropathy; Neuroinflammation; PPAR-; FENOFIBRIC ACID; PALMITOYLETHANOLAMIDE; ALPHA; PAIN; AGONIST; PLASMA;

D O I：

10.1016/j.bbi.2021.01.004

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-alpha (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-1 beta 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.

引用

页码：172 / 185

页数：14

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