Chemotherapy-induced peripheral neuropathy (CIPN) is a side effect of chemotherapics, such as taxanes, vinca alkaloids, and platinum compounds. Sensory neuropathy causes symptoms such as pain, allodynia, loss of sensation, paresthesia, numbness, tingling, and gait disturbance [1]. CIPN can result in significant loss of functional abilities and negatively impact quality of life, leading to lowering of the dose and discontinuation of assumption, and ultimately affecting overall survival rates [2]. Some chemotherapeutic drugs have been associated with a higher prevalence and duration of CIPN, such as taxanes and oxaliplatin treatment, which can last up to six months or two years after chemotherapy [1].

The mechanisms described so far are diverse and target various components of the PNS. The Dorsal Root ganglion (DRG), which lacks an efficient blood–brain barrier (BBB) [3], is prone to neurotoxic damage and can account for the sensory symptoms seen in CIPN. Pt compounds trigger DNA damage through Pt adducts and cause changes in the nucleoli of DRG sensory neurons, affecting the transcription machinery [4]. The accumulation of taxanes and vinca alkaloids in the DRG seems to produce nucleolar abnormalities [5] and modifications in the neurofilaments [6]. They also affect microtubule conformation through tubulin acetylation (Figure 1) [7]. Bortezomib (BTZ) [8] and vinca alkaloids [9] modify axonal transport by decreasing the supply of trophic factors and energy production, or by increasing Wallerian-degeneration and causing neurological damage, which is often permanent. Energy depletion in axons due to mitochondrial damage may contribute to the neurotoxicity exerted by different chemotherapics [10,11,12]. BTZ affects the integrity of the endoplasmic reticulum, mainly in Schwann cells [8], thus causing degeneration of the myelin sheath. The modulation of axonal ion channels may also be involved in CIPN. Dysfunction in Na⁺ channels, mediated mainly by oxaliplatin, but also by paclitaxel and vincristine, can lead to an increase in Na⁺ currents in the DRG, predisposing it to paresthesia [13,14,15]. Moreover, Ca²⁺ and K⁺ channels are related to paclitaxel [16] and oxaliplatin toxicity [17], respectively. In addition, alterations in proteins involved in Ca²⁺ signaling (such as calpains and caspases) lead to apoptotic phenomena in the DRG [18]. Changes in the expression levels of transient receptor potential channels (TRPV, TRPA, and TRPM), as well as in molecules related to glutamate signaling induced by Pt compounds, resulting from treatment with paclitaxel and BTZ [19,20,21,22,23], lead to hyper-responsiveness of nociceptors, rendering patients prone to neuropathic pain and peripheral neuropathy development. Chemotherapics also induce increased expression of mitogen-activated protein kinases (MAPKs), leading to neurotoxicity [24]. Vincristine, paclitaxel, and BTZ cause inflammation due to an increase in pro-inflammatory cytokines in the peripheral nerves and the number of antigen presenting cells in the skin [16,25]. Furthermore, the production of reactive oxygen species (ROS), combined with an increase in Ca²⁺ in the DRG, is a common following chemotherapy and leads to neuronal cytotoxicity [26,27,28].

Among the players in neuropathic pain, inflammation has been indicated as a potential common driver of CIPN. Several pieces of evidence have demonstrated a chemotherapy-induced increase in peripheral pro-inflammatory cytokines and a strong correlation with peripheral neuropathy [29,30]. At present, there is no adequate strategy to prevent CIPN, although there are active drugs for treating CIPN, such as duloxetine, that have displayed a moderate effect on CIPN.

CIPN is a dose-limiting side effect of chemotherapy that affects 30–40% of patients undergoing treatment [31]. It has been described as a functional impairment of neurons characterized by oxidative stress, inflammation, apoptosis, and electrophysiological failure.

It is generally accepted that, at the neuronal level, chemotherapeutic drugs damage microtubules and affect microtubule-based axonal transport, damage mitochondrial function, alter ionic homeostasis, or directly target DNA [32], leading to peripheral nerve degeneration or small fiber neuropathy. Taxanes and vinca alkaloids exhibit an antiproliferative effect by disrupting mitotic spindles and causing cell cycle arrest [32]. Platinum agents are known to cause CIPN by damaging the DRG through mitochondrial dysfunction and apoptosis, while also causing DNA damage or oxidative stress [33]. New drugs, such as bortezomib, eribulin, and ixabepilone, are also correlated with significant incidences of CIPN by affecting tubulin polymerization [33,34]. Glial cells seem to play a crucial role in CIPN. Alterations of Schwann cells, satellite cells in the DRG, and astrocytes in the spinal cord after chemotherapy lead to the activation of apoptosis [35]. Loss of glial cells results in a decrease in the protection and sustainment of nerve fibers and consequent defects in the propagation of the action potential [36]. Numerous findings indicate that CIPN, in addition to causing morphological changes, triggers the involvement of the inflammation and immune responses. Chemotherapy can cause mitochondrial DNA adducts and defects in electron transport chain proteins, leading to mitochondrial dysfunction [37,38]. This event is accompanied by disequilibrium in the redox potential and an increase in ROS within cells [37]. These reactive species can trigger perturbations in peripheral neurons, such as mitochondrial apoptosis, inflammation, and subsequent nerve degeneration [37,38]. ROS can also damage biomolecules such as phospholipids, resulting in demyelination, oxidized proteins, and an increase in carbonyl by-products, which can activate transient receptor potential vanilloid (TRPV) channels, impair antioxidant enzymes, and destroy microtubules [37]. Adducts to nuclear DNA and peroxynitrite create strand breaks, promoting neuronal apoptosis [39,40]. Intracellular ROS can also cause peripheral nociceptor over-excitation by increasing pro-inflammatory mediators (interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), bradykinin, and nerve growth factors) [37,41]. All these metabolic, bioenergetic, and functional impairments lead to the development and maintenance of peripheral neuropathic injuries in neurons [37]. On the basis of these observations, it appears that preventative therapies for CIPN are urgently required for patients receiving chemotherapy.

Although many strategies have been developed, no specific intervention is presently recommended for the prevention or management of CIPN. In many patients, chemotherapy is discontinued due to CIPN, which increases the risk for patients. No efficient treatment options are presently available for CIPN because its exact pathophysiological mechanisms are not yet fully elucidated. Most of the pharmacologic treatments available for neuropathic pain include tricyclic antidepressants and anticonvulsants, which are minimally effective for CIPN and/or have substantial side effects [42,43,44]. At present, only duloxetine is recommended by the American Society of Clinical Oncology (ASCO) for CIPN treatment, based on a modest positive result obtained in one randomized controlled trial (RCT) [45].

3. Cytokine Signaling in CIPN