1. Introduction

Peripheral neuropathies (PN) can be inherited or acquired as a result of a pathological process or trauma ^[1]. Causes of acquired PN can have multiple origins such as autoimmune, toxic, alcoholic, diabetic, cancerous, chemo-induced, and traumatic, including crushing, constriction, stretching, and complete nerve sectioning ^{[2][3][4][5][6]}. However, the precise ethology of some neuropathies is sometimes not identified. Clinicians refer to these conditions as idiopathic neuropathies. PN may affect a single nerve (mononeuropathy), two or more nerves in different areas (multiple mononeuropathy), or many nerves (polyneuropathy). Carpal tunnel syndrome and facial paralysis are examples of mononeuropathy. Most people with PN have polyneuropathy affecting longer nerve fibers (length-dependent polyneuropathy)^[7].

The symptomatology is very diverse depending on the type of nerve fibers affected. In the case of sensory fiber damage, symptoms are dependent on the caliber and size of the nerve fibers. These symptoms are generally progressive numbness, tingling in the feet or hands which may extend to the legs and arms, or even sharp, throbbing, icy or burning pain, stinging sensations and extreme sensitivity to touch. In the case of motor fiber damage, the most common symptoms are a lack of motor coordination and falls, muscle weakness or paralysis. If autonomic nerves are affected, signs and symptoms may include: heat intolerance and alterations in sweating, dermal problems, intestinal, bladder or digestive problems, but also changes in blood pressure, which can lead to dizziness^[1][2].

The major clinical problem in PN, in addition to the difficulties in diagnosing and understanding pathological mechanisms, is that they are poorly treated with currently available therapeutics.

2. Use Curcumin in Treatment of PN

Recently, interest in the role of dietary antioxidants, such as polyphenols, in human health has led to a great deal of research on their potential as possible treatment of many inflammatory diseases. Among these polyphenols, curcumin which has long been used in traditional Asian cuisine and medicine, is an attractive molecule. However, curcumin has a very low bioavailability and a very fast metabolism. Thus, very high doses are required to achieve therapeutic effects given the uncertainty that curcumin will reach the target organ.

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione], also known as diferuloylmethane, is a polyphenol present in the rhizome of Curcuma longa^[8]. Curcuma longa powder is a spice known as turmeric and used in the preparation of curry. Turmeric powder is an orange-yellow crystalline compound that is used as a food coloring agent ^[8]. Traditionally, turmeric powder has been used in Asian countries as a medicinal preparation to combat several diseases because of its antioxidant, anti-inflammatory, antimicrobial, anticancer, and neuroprotective properties ^{[8][9][10][11][12]}. Over the past 50 years, it has been shown that most of the effects of Curcuma longa are primarily due to curcumin, with potential beneficial properties against diabetes, allergies, arthritis, neuropathies, and other chronic diseases^[13]. However, there are other components of Curcuma longa that, together with curcumin, form the curcuminoid group^[14]. These are demethoxycurcumin and bis-demethoxycurcumin. The curcuminoid group constitutes about 5% of the total components of Curcuma longa and curcumin is the most abundant of this group with 77% ^[14].

Curcumin is a lipophilic molecule that is rapidly metabolized, leading to low bioavailability. Thus, several studies propose the use of new formulations of curcumin such as emulsions or nanoparticles to improve systemic bioavailability. These approaches are very interesting in the context of several PN in which nerves are affected (diabetes, alcohol, chemotherapy, genetic mutations.)^[15]. Moreover, these approaches allow to decrease and better control the dose of curcumin used, although it has no proven toxicity. In this respect, there is growing evidence that curcumin nanoparticles have a better effect on oxidative stress than conventional curcumin^[15]. Other authors propose in the case of localized lesions, as in the case of traumatic lesion, transection or local inflammation, the use of biofunctionalized conduit with curcumin or local administration at the site of the lesion^[16]. Thus, the use of these new approaches (nanoparticles, tubes.) allows a progressive diffusion of curcumin in the target organism or organ. This makes it possible to avoid the “one shot” effect produced by a conventional injection. This diffusion is all the more interesting as it allows a better reduction of inflammation and oxidative stress, which are processes that last over time and can be chronic. Thus, curcumin because of its anti-inflammatory, antioxidant, anti-ER-stress, and neuro-protective properties is the perfect candidate for the treatment of PN^[9].

In addition, its lipophilic nature allows it to be integrated into the myelin sheath, thus exerting a powerful antioxidant effect. The role of curcumin on the ER is not very clear at the moment. In our opinion, it represents a major challenge for the future. Indeed, a growing number of studies show the key role of this organelle in the development of numerous PN (diabetes, alcohol, chemotherapy, genetic mutations.). Thus, because of its numerous biological properties, curcumin reduces tissue damage or improves tissue repair (nerve, muscle, DRG) in many PN. These effects are also reflected at the behavioral level by reducing the signs of pain, improving sensory and motor recovery. However, despite a large number of pre-clinical studies (both in vitro and in vivo) on the subject and a large amount of laboratory evidence of curcumin’s efficacy, studies in humans are sorely lacking. Indeed, to date, only four clinical studies have been specifically conducted in humans in the field of PN. These studies, although encouraging, are sometimes carried out on too few subjects and therefore make it difficult to objectify the use of curcumin clinically for PN^{[17][18][19][20]}. However, the large number of studies on inflammatory pain represents hope for the future use of this molecule for the treatment of neuropathies. We therefore believe that the advent of new curcumin formulations represents a key milestone in the treatment of PN in humans.

Figure1. A suggested model summarizing the sites of action of curcumin in peripheral neuropathies as reported in the literature: Curcumin reduces neuropathic pain and improves sensitivity in in vivo models of PN, by improving sensory nerve conduction velocity (SNCV), reducing the loss of neurons and satellite cells in dorsal roots ganglia (DRG), and promoting the regrowth of sensory nerve fibers. In addition, curcumin improves motor functions in in vivo models of PN, by improving motor nerve conduction velocity (MNCV), reducing nerve fibers demyelination, loss of motor neurons in spinal cord, muscle atrophy and neurogenic lesions, and improving motor nerves fibers regrowth.