A Fenofibrate Diet Prevents Paclitaxel-Induced Peripheral Neuropathy in Mice

SIMPLE SUMMARY: Paclitaxel, a drug used in the treatment of malignancies such as lung, ovarian and breast cancer, often produces severe side effects, among which is peripheral neuropathy. This neuropathy involves diffuse or localized pain, notably burning pain, cold and mechanical hyperexcitability. Recently, fenofibrate, a Food and Drug Administration (FDA)-approved drug for the treatment of dyslipidemia, has been shown to reduce the severity of symptoms in other forms of peripheral neuropathy. In the current work, we tested whether fenofibrate could reverse mechanical and cold hypersensitivity and improve motivation and the reduction in nerve conduction in a mouse model of paclitaxel-induced neuropathy. Our behavioral, histological and molecular assessments indicate that fenofibrate prevents the development of paclitaxel-induced neuropathy. Taken together, our studies support the therapeutic potential of fenofibrate in the prevention of paclitaxel-induced neuropathy and suggest the possible repurposing of this drug for this purpose in the clinic. 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.