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

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.

• Authors: 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
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 93 Pg. 172-185 (03 2021) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 33434562 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• PPAR alpha
• Paclitaxel

Topics

• Animals
• Female
• Male
• Mice
• Mice, Inbred C57BL
• PPAR alpha
• Paclitaxel
• Peripheral Nervous System Diseases (chemically induced, drug therapy)