A Fenofibrate Diet Prevents Paclitaxel-Induced Peripheral Neuropathy in Mice

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.

Formulated Curcumin Prevents Paclitaxel-Induced Peripheral Neuropathy through Reduction in Neuroinflammation by Modulation of α7 Nicotinic Acetylcholine Receptors

“…At 21 days after paclitaxel injection, electrophysiological studies were conducted as previously described [7]. Briefly, dorsal caudal nerve conduction was recorded in the tail by stimulation and recording-needle electrodes connected to the PowerLab/26T device (ADInstruments, Colorado Springs, CO, USA).…”

“…After euthanasia of the mice at D22, the dorsal-root ganglia (DRG) and spinal cord were collected. The preparation of the samples was previously described in [7]. Measurements of the cytokine-expression levels present in the homogenates of DRG and the spinal cord were performed with a Bio-Plex assay plate (Bio-Plex Pro Mouse Cytokine 23-plex Assay, Bio-Rad, CA, USA).…”

“…Among the chemotherapeutic agents used to treat solid tumors, paclitaxel is one of the most widely administered. Multiple mechanisms have been reported to mediate the neurotoxicity of paclitaxel, such as local degeneration of distal axon, changes in mitochondrial ultrastructure and transport, increased neuroinflammation, and oxidative stress in the spinal cord and dorsal-root ganglia (DRG) [5][6][7].…”

Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy

“…Inflammatory cytokines (e.g., interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)) and chemokines (e.g., chemokine (C-X-C motif) ligand (CXCL) family) were elevated in the peripheral sites, spinal cord, and of paclitaxeltreated animals, and many agents reduced the peripheral neuropathy symptoms via their anti-inflammatory effects [19,21,22,24,25,27,28,[32][33][34][35][36][37][38][39]41,42,[44][45][46][47][49][50][51][52][53][54]56]. Activations of astrocytes and microglia were also observed in the spinal dorsal horn after paclitaxel administrations, and many agents including minocycline attenuated PIPN via the inhibition of these spinal changes and prevented neurological damage [40,43,44,48].…”

The Beneficial Effects of Ultramicronized Palmitoylethanolamide in the Management of Neuropathic Pain and Associated Mood Disorders Induced by Paclitaxel in Mice

“…In fact, PEA efficacy in chemotherapy-induced neuropathy has already been evaluated by previous studies via the oxaliplatin- [ 40 ] and PTX-induced CIPN model [ 41 ]. In particular, the last study has shown the effect to be mediated by PPAR-α, whose antagonism (i.e., through fenofibrate) is indeed known to reduce neuroinflammation in PTX-induced neuropathy [ 42 ].…”