A Fenofibrate Diet Prevents Paclitaxel-Induced Peripheral Neuropathy in Mice

Martial Caillaud; Nipa H Patel; Wisam Toma; Alyssa White; Danielle Thompson; Jared Mann; Tammy H Tran; Jane L Roberts; Justin L Poklis; John W Bigbee; Xianjun Fang; David A Gewirtz; M Imad Damaj

doi:10.3390/cancers13010069

A Fenofibrate Diet Prevents Paclitaxel-Induced Peripheral Neuropathy in Mice

Cancers (Basel). 2020 Dec 29;13(1):69. doi: 10.3390/cancers13010069.

Authors

Affiliations

¹ Department of Pharmacology and Toxicology and Translational Research Initiative for Pain and Neuropathy, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23284, USA.
² Departments of Pharmacology and Toxicology and Medicine and Massey Cancer Center, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23284, USA.
³ Department of Anatomy and Neurobiology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA.
⁴ Department of Biochemistry & Molecular Biology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA.

Abstract

Background: Paclitaxel-induced peripheral neuropathy (PIPN) is a major adverse effect of this chemotherapeutic agent that is used in the treatment of a number of solid malignancies. PIPN leads notably to burning pain, cold and mechanical allodynia. PIPN is thought to be a consequence of alterations of mitochondrial function, hyperexcitability of neurons, nerve fiber loss, oxidative stress and neuroinflammation in dorsal root ganglia (DRG) and spinal cord (SC). Therefore, reducing neuroinflammation could potentially attenuate neuropathy symptoms. Peroxisome proliferator-activated receptor-α (PPAR-α) nuclear receptors that modulate inflammatory responses can be targeted by non-selective agonists, such as fenofibrate, which is used in the treatment of dyslipidemia.

Methods: Our studies tested the efficacy of a fenofibrate diet (0.2% and 0.4%) in preventing the development of PIPN. Paclitaxel (8 mg/kg) was administered via 4 intraperitoneal (i.p.) injections in C57BL/6J mice (both male and female). Mechanical and cold hypersensitivity, wheel running activity, sensory nerve action potential (SNAP), sciatic nerve histology, intra-epidermal fibers, as well as the expression of PPAR-α and neuroinflammation were evaluated in DRG and SC.

Results: Fenofibrate in the diet partially prevented the development of mechanical hypersensitivity but completely prevented cold hypersensitivity and the decrease in wheel running activity induced by paclitaxel. The reduction in SNAP amplitude induced by paclitaxel was also prevented by fenofibrate. Our results indicate that suppression of paclitaxel-induced pain by fenofibrate involves the regulation of PPAR-α expression through reduction in neuroinflammation. Finally, co-administration of paclitaxel and the active metabolite of fenofibrate (fenofibric acid) did not interfere with the suppression of tumor cell growth or clonogenicity by paclitaxel in ovarian and breast cancer cell lines.

Conclusions: Taken together, our results show the therapeutic potential of fenofibrate in the prevention of PIPN development.

Keywords: PPAR-α; fenofibrate; neuropathic pain; paclitaxel; peripheral neuropathy.

Abstract

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