Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy; cause and effect?

Abstract

Cancer is the second leading cause of death worldwide and is a major global health burden. Significant improvements in survival have been achieved, due in part to advances in adjuvant antineoplastic chemotherapy. The most commonly used antineoplastics belong to the taxane, platinum, and vinca alkaloid families. While beneficial, these agents are frequently accompanied by severe side effects, including chemotherapy-induced peripheral neuropathy (CPIN). While CPIN affects both motor and sensory systems, the majority of symptoms are sensory, with pain, tingling, and numbness being the predominant complaints. CPIN not only decreases the quality of life of cancer survivors but also can lead to discontinuation of treatment, thereby adversely affecting survival. Consequently, minimizing the incidence or severity of CPIN is highly desirable, but strategies to prevent and/or treat CIPN have proven elusive. One difficulty in achieving this goal arises from the fact that the molecular and cellular mechanisms that produce CPIN are not fully known; however, one common mechanism appears to be changes in ion channel expression in primary afferent sensory neurons. The processes that underlie chemotherapy-induced changes in ion channel expression and function are poorly understood. Not all antineoplastic agents directly affect ion channel function, suggesting additional pathways may contribute to the development of CPIN Indeed, there are indications that these drugs may mediate their effects through cellular signaling pathways including second messengers and inflammatory cytokines. Here, we focus on ion channelopathies as causal mechanisms for CPIN and review the data from both pre-clinical animal models and from human studies with the aim of facilitating the development of appropriate strategies to prevent and/or treat CPIN.

Figure 1.

Oxaliplatin-induced mechanical and cold hypersensitivity is reversed by ivabradine. (a) (Left) A single dose of oxaliplatin (6 mg/kg) causes a steady decrease in mechanical threshold over four days. On the fourth day, intraperitoneal administration of ivabradine (IVA; 5 mg/kg) or gabapentin (G.pen; 50 mg/kg) causes a significant increase in mechanical threshold when compared to vehicle-treated mice. (Right) Mean difference in mechanical threshold on Day 4 compared to pre-oxaliplatin levels for ivabradine, gabapentin, and vehicle-treated animals. Only ivabradine (open bar) returns the mechanical threshold fully to baseline levels. N = 10 for each group. (b) and (c) Number of jumps made by mice in response to a cold ramp (cooling from 20℃ to 0℃ at 2℃/min) before (basal) and four days after a single dose of oxaliplatin (Oxa; 6 mg/kg) with pre-administration (30 min) of vehicle (b) or ivabradine (c; 10 mg/kg). (d) Only the vehicle-treated group shows a significant difference in the number of jumps pre-post oxaliplatin (ΔAUC, difference in total number of jumps in response to temperature ramp), N = 10 for each group. Figure modified from Young et al. with permission.

Figure 2.

Putative sites of action on peripheral sensory neurons for chemotherapy-induced neuropathy. Major classes of antineoplastics are listed (also shown is bortezomib, a proteasome inhibitor that is used for the treatment of multiple myeloma, which is also associated with CIPN). Primary afferents project to the distinct Laminae of Rexed (schematically illustrated) of the superficial spinal cord dorsal horn (DH) in a topographic fashion; Aδ nociceptors (I), C/Aδ peptidergic fibers (I-II_outer), C non-peptidergic fibers (II), Aδ hair follicle afferents (II_inner-III), and Aβ hair follicle and tactile afferents (II_inner-V). Alterations in neuronal excitability can arise from changes in ion channel function at the level of the cell soma (located in the dorsal root ganglion; DRG), the axon terminal, or along the axon itself.