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

Martial Caillaud; Nipa H Patel; Alyssa White; Mackinsey Wood; Katherine M Contreras; Wisam Toma; Yasmin Alkhlaif; Jane L Roberts; Tammy H Tran; Asti B Jackson; Justin Poklis; David A Gewirtz; M Imad Damaj

doi:10.1016/j.bbi.2021.01.004

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

Brain Behav Immun. 2021 Mar:93:172-185. doi: 10.1016/j.bbi.2021.01.004. Epub 2021 Jan 9.

Affiliations

¹ Department of Pharmacology and Toxicology and Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, USA. Electronic address: martial.caillaud@vcuhealth.org.
² Department of Pharmacology and Toxicology and Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, USA.
³ Department of Pharmacology and Toxicology and Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, USA; Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, USA. Electronic address: m.damaj@vcuhealth.org.

Abstract

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.

Keywords: Chemotherapy; Fibrates; Neuroinflammation; PPAR-⍺; Peripheral neuropathy.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Female
Male
Mice
Mice, Inbred C57BL
PPAR alpha*
Paclitaxel
Peripheral Nervous System Diseases* / chemically induced
Peripheral Nervous System Diseases* / drug therapy

Substances

PPAR alpha
Paclitaxel

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

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