Peripheral neuropathies (PN) can be triggered after metabolic diseases, traumatic peripheral nerve injury, genetic mutations, toxic substances, and/or inflammation. PN is a major clinical problem, affecting many patients and with few effective therapeutics. Recently, interest in natural dietary compounds, such as polyphenols, in human health has led to a great deal of research, especially in PN. Curcumin is a polyphenol extracted from the root of Curcuma longa. This molecule has long been used in Asian medicine for its anti-inflammatory, antibacterial, and antioxidant properties. However, like numerous polyphenols, curcumin has a very low bioavailability and a very fast metabolism. This review addresses multiple aspects of curcumin in PN, including bioavailability issues, new formulations, observations in animal behavioral tests, electrophysiological, histological, and molecular aspects, and clinical trials published to date. The, review covers in vitro and in vivo studies, with a special focus on the molecular mechanisms of curcumin (anti-inflammatory, antioxidant, anti-endoplasmic reticulum stress (anti-ER-stress), neuroprotection, and glial protection). This review provides for the first time an overview of curcumin in the treatment of PN. Finally, because PN are associated with numerous pathologies (e.g., cancers, diabetes, addiction, inflammatory disease...), this review is likely to interest a large audience.

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.

Paclitaxel is widely used in the treatment of various types of solid malignancies. Paclitaxel-induced peripheral neuropathy (PIPN) is often characterized by burning pain, cold, and mechanical allodynia in patients. Currently, specific pharmacological treatments against PIPN are lacking. Curcumin, a polyphenol of Curcuma longa, shows antioxidant, anti-inflammatory, and neuroprotective effects and has recently shown efficacy in the mitigation of various peripheral neuropathies. Here, we tested, for the first time, the therapeutic effect of 1.5% dietary curcumin and Meriva (a lecithin formulation of curcumin) in preventing the development of PIPN in C57BL/6J mice. Curcumin or Meriva treatment was initiated one week before injection of paclitaxel and continued throughout the study (21 days). Mechanical and cold sensitivity as well as locomotion/motivation were tested by the von Frey, acetone, and wheel-running tests, respectively. Additionally, sensory-nerve-action-potential (SNAP) amplitude by caudal-nerve electrical stimulation, electronic microscopy of the sciatic nerve, and inflammatory-protein quantification in DRG and the spinal cord were measured. Interestingly, a higher concentration of curcumin was observed in the spinal cord with the Meriva diet than the curcumin diet. Our results showed that paclitaxel-induced mechanical hypersensitivity was partially prevented by the curcumin diet but completely prevented by Meriva. Both the urcumin diet and the Meriva diet completely prevented cold hypersensitivity, the reduction in SNAP amplitude and reduced mitochondrial pathology in sciatic nerves observed in paclitaxel-treated mice. Paclitaxel-induced inflammation in the spinal cord was also prevented by the Meriva diet. In addition, an increase in α7 nAChRs mRNA, known for its anti-inflammatory effects, was also observed in the spinal cord with the Meriva diet in paclitaxel-treated mice. The use of the α7 nAChR antagonist and α7 nAChR KO mice showed, for the first time in vivo, that the anti-inflammatory effects of curcumin in peripheral neuropathy were mediated by these receptors. The results presented in this study represent an important advance in the understanding of the mechanism of action of curcumin in vivo. Taken together, our results show the therapeutic potential of curcumin in preventing the development of PIPN and further confirms the role of α7 nAChRs in the anti-inflammatory effects of curcumin.

Amyloid-β (Aβ) plays a critical role in Alzheimer’s disease (AD) and its accumulation in the brain is pivotal to disease progression and precedes memory and neuronal loss. Besides the severely handicapping brain symptoms, AD patients display early gastro-intestinal (GI) manifestations such as upper and lower GI dysmotility, in particular constipation. Although there is increasing evidence of Aβ accumulation in the gut, its pathogenic effects on enteric nervous system (ENS) connectivity and gut function as well as underlying pathophysiological mechanisms are poorly understood. Furthermore, studies have reported a gut to brain transmission of Aβ that causes memory deficits in mice. Therefore, identifying therapeutics which can reduce Aβ accumulation in the gut at an early stage of the disease could have the advantage of slowing or even reversing disease progression before severe alterations or irreversible damages at both intestinal and brain levels. Hence, in this study, we investigated the capacity of the short-fatty acid butyrate to restore Aβ-driven alteration of ENS connectivity and gut-brain functions in the SAMP8 mouse model of AD. Here we show that SAMP8 mice display a gut amyloid pathology, an alteration of ENS connectivity and gut defects prior to memory decline. BACE1, an Aβ-producing enzyme, expression and activity are increased whereas neprilysin, an Aβ-degrading enzyme, is decreased in the gut of SAMP8 mice, indicating a rise in the Amyloid Precursor Protein (APP) holoprotein processing and a reduction of Aβ clearance which promote an amyloidosis. In primary ENS cultures, Aβ causes a degradation of synaptic-associated proteins EphB2 and synaptophysin, leading to an alteration of ENS connectivity. In wild-type mice, intra-colon delivery of Aβ alters ENS connectivity and causes subsequent GI symptoms, recapitulating the phenotype of the SAMP8 mouse model of aging and AD. Moreover, Aβ impairs ENS connectivity in human induced pluripotent stem cell (iPSC)-derived intestinal organoids and explant cultures of human colon, indicating that Aβ causes ENS lesions in models of the human gut. Butyrate, a short-chain fatty acid derived from bacterial metabolism, reduces Aβ secretion and preserves enteric neuronal connectivity in vitro and in vivo, and blocks Aβ accumulation in the gut, brain and plasma in SAMP8 mice. In addition, butyrate ameliorates neuroinflammation and prevents gut dysfunction and memory deficit. Collectively, these findings suggest that Aβ promotes gut symptoms through alteration of ENS connectivity and butyrate counteracts these impairments with an amelioration of neuroinflammation and memory function in AD model.