Abstract
Peripheral neuropathies are characterized by nerves damage and axonal loss, and they could be classified in hereditary or acquired forms. Acquired peripheral neuropathies are associated with several causes, including toxic agent exposure, among which the antineoplastic compounds are responsible for the so called Chemotherapy-Induced Peripheral Neuropathy (CIPN). Several clinical features are related to the use of anticancer drugs which exert their action by affecting different mechanisms and structures of the peripheral nervous system: the axons (axonopathy) or the dorsal root ganglia (DRG) neurons cell body (neuronopathy/ganglionopathy). In addition, antineoplastic treatments may affect the blood brain barrier integrity, leading to cognitive impairment that may be severe and long-lasting. CIPN may affect patient quality of life leading to modification or discontinuation of the anticancer therapy. Although the mechanisms of the damage are not completely understood, several hypotheses have been proposed, among which neuroinflammation is now emerging to be relevant in CIPN pathophysiology. In this review, we consider different aspects of neuro-immune interactions in several CIPN preclinical studies which suggest a critical connection between chemotherapeutic agents and neurotoxicity. The features of the neuroinflammatory processes may be different depending on the type of drug (platinum derivatives, taxanes, vinca alkaloids and proteasome inhibitors). In particular, recent studies have demonstrated an involvement of the immune response (both innate and adaptive) and the stimulation and secretion of mediators (cytokines and chemokines) that may be responsible for the painful symptoms, whereas glial cells such as satellite and Schwann cells might contribute to the maintenance of the neuroinflammatory process in DRG and axons respectively. Moreover, neuroinflammatory components have also been shown in the spinal cord with microglia and astrocytes playing an important role in CIPN development. Taking together, better understanding of these aspects would permit the development of possible strategies in order to improve the management of CIPN.
Highlights
Chemotherapy-induced peripheral neurotoxicity (CIPN) may occur in patients undergoing antineoplastic therapy, frequently being the most severe side-effect
Since activation transcription factor 3 (ATF3) plays an important role downstream Toll Like receptors (TLRs) activation, further studies deepened the implication of this signaling pathway in the Chemotherapy-Induced Peripheral Neuropathy (CIPN) pathogenesis. These studies on the role of TLR3 and 4 and their adapter proteins (MyD88 and TRIF) showed that CDDP-induced mechanical allodynia was reduced in trl3-/- and tlr4-/- mice compared to WT animals and was abolished in animals that completely lack TLR pathways (Myd88/Triflps2 mice). These results suggest that MyD88 and TRIF signaling cascades triggered by the activation of TLR4 and TLR3, participated in the onset of neuropathic pain induced by CDDP [39, 40]
Despite literature data indicate some controversial results, which may be attributed to the different animal models used, taken together all these findings suggest that OHP-induced neuroinflammation retrieved in the dorsal horn of the spinal cord (DHSC) might play a critical role in the onset of OHP-related neuropathic pain
Summary
Chemotherapy-induced peripheral neurotoxicity (CIPN) may occur in patients undergoing antineoplastic therapy, frequently being the most severe side-effect. CIPN is characterized by severe and long lasting symptoms that might affect daily activities and impact on patient quality of life. This clinical situation leads to drug schedule modification, or even withdrawal, potentially affecting patient’s survival and clinical outcome [1,2,3,4]. The chemotherapy drugs act on different structures of the peripheral nervous system (PNS), due to both the reduced blood-nervous tissue barrier efficacy and the presence of fenestrated capillaries in dorsal root ganglia (DRG), targeting the axons, inducing a length-dependent axonopathy, or DRG neurons, leading to a neuronopathy [5, 6]. CIPN becomes a chronic condition and the symptoms may persist or even progress for months after the end of the therapy, a phenomenon known as “coasting” [10]
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