Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common off-target adverse effects caused by various chemotherapeutic agents, such as cisplatin, oxaliplatin, paclitaxel, vincristine and bortezomib. CIPN is characterized by a substantial loss of primary afferent sensory axonal fibers leading to sensory disturbances in patients. An estimated of 19-85% of patients developed CIPN during the course of chemotherapy. The lack of preventive measures and limited treatment options often require a dose reduction or even early termination of life-saving chemotherapy, impacting treatment efficacy and patient survival. In this Review, we summarized the current understanding on the pathogenesis of CIPN. One prominent change induced by chemotherapeutic agents involves the disruption of neuronal cytoskeletal architecture and axonal transport dynamics largely influenced by the interference of microtubule stability in peripheral neurons. Due to an ineffective blood-nerve barrier in our peripheral nervous system, exposure to some chemotherapeutic agents causes mitochondrial swelling in peripheral nerves, which lead to the opening of mitochondrial permeability transition pore and cytochrome c release resulting in degeneration of primary afferent sensory fibers. The exacerbated nociceptive signaling and pain transmission in CIPN patients is often linked the increased neuronal excitability largely due to the elevated expression of various ion channels in the dorsal root ganglion neurons. Another important contributing factor of CIPN is the neuroinflammation caused by an increased infiltration of immune cells and production of inflammatory cytokines. In the central nervous system, chemotherapeutic agents also induce neuronal hyperexcitability in the spinal dorsal horn and anterior cingulate cortex leading to the development of central sensitization that causes CIPN. Emerging evidence suggests that the change in the composition and diversity of gut microbiota (dysbiosis) could have direct impact on the development and progression of CIPN. Collectively, all these aspects contribute to the pathogenesis of CIPN. Recent advances in RNA-sequencing offer solid platform for in silico drug screening which enable the identification of novel therapeutic agents or repurpose existing drugs to alleviate CIPN, holding immense promises for enhancing the quality of life for cancer patients who undergo chemotherapy and improve their overall treatment outcomes.

Keywords: chemotherapy-induced peripheral neuropathy; cold allodynia; dorsal root ganglion; intraepidermal nerve fibers; mechanical allodynia.

Figure 1

Animal behavioral assessment for the evaluation of peripheral neuropathy. (A) Both manual (left panel) and electronic von Frey filament tests are widely used to evaluate mechanical allodynia in mouse and rat models of chemotherapy-induced peripheral neuropathy (CIPN). Before the behavioral test, the tested animals are placed into wire mesh cages on an elevated platform for at least 30 min. For manual von Frey filament test (left panel), a set of von Frey monofilaments that are calibrated to deliver a fixed force is applied to the lateral plantar surface of the hindpaw for 2 s. A brisk paw withdrawal, licking or shaking is considered as a positive response to the stimulus. For electronic von Frey (right panel), the device delivers a gradually increasing force to the lateral plantar surface of the hindpaw. The force at which the animal shows a paw withdrawal response is recorded automatically by the aesthesiometer. (B) Tail flick test (left panel), hot plate test (middle panel) and Hargreaves test (right panel) are commonly used to assess thermal hyperalgesia. For tail flick test, a source of radiant heat is applied to the tail, and the time required to elicit tail flicking and twitch is recorded. For hot plate test, the tested animal is placed on a hot surface, and the latency for the animal to lick its hindpaw or jump out of the plate is recorded. For Hargreaves test, the tested animals are placed in an enclosed glass pane, and a radiant heat source is placed under the hindpaw of the animals. The latency for the animals to elicit a withdrawal response is recorded. (C) Cold plate test (left panel) and acetone drop tests (right panel) are widely used animal behavioral assessments for cold allodynia. For cold plate test, the tested animal is placed on a cold surface, and the time for the animal to provoke typical nociceptive responses (licking, paw withdrawal, shaking or jumping) is recorded. For acetone drop test, a small drop of acetone is applied directly to the hindpaw of the tested animal, and the duration of paw withdrawal, licking or flinching is recorded. BioRender.com

Figure 2

Potential molecular mechanisms underlying the development of chemotherapy-induced peripheral neuropathy (CIPN). (A) Chemotherapeutic agents induce drastic changes in the neuronal cytoskeletal architecture, resulting in axonal fragmentation in the sensory neurons. The disrupted microtubule cytoskeleton and integrity of sensory neurons also impaired the axonal transport of mitochondria and mRNA. (B) Chemotherapeutic agents induce mitochondrial swelling and vacuolation in both myelinated and unmyelinated sensory fibers in the peripheral nerve, resulting in reduced ATP production in the mitochondria. Also, chemotherapeutic agents induce rapid mitochondrial depolarization and cytochrome c release from mitochondria. (C) Chemotherapeutic agents induce significant changes in the expression of various ion channels—increased expression of Na_v, Ca_v, NKCC1 and TRP channels while decreased expression of K⁺ channels. These collectively increase the neuronal excitability in DRG neurons leading to pain hypersensitivity. (D) Chemotherapeutic agents induce local inflammation in the epidermis of glabrous hindpaw skin, resulting in the degeneration of primary afferent sensory fibers. Also, chemotherapeutic agents induce neuroinflammation in the dorsal root ganglion and dorsal horns of the spinal cord, leading to augmented production of pro-inflammatory cytokines and chemokines. (E) It is believed that chemotherapeutic agents also lead to the development of central sensitization, an increase in the responsiveness to nociception in the CNS to afferent inputs, which in turn leads to increased neuronal excitability in the spinal dorsal horn and brain (e.g., anterior cingulate cortex). (F) Recent findings proposed that chemotherapeutic agents induce a drastic change in the gut microbiota which eventually led to the development of pain hypersensitivity in CIPN patients. Therapeutic interventions such as probiotics aiming to restore the gut microbiota composition alleviated the mechanical and cold hypersensitivity after treatment of CIPN-causing agents. BioRender.com