Axonal degeneration in chemotherapy-induced peripheral neurotoxicity: clinical and experimental evidence

Abstract

Multiple pathological mechanisms are involved in the development of chemotherapy-induced peripheral neurotoxicity (CIPN). Recent work has provided insights into the molecular mechanisms underlying chemotherapy-induced axonal degeneration. This review integrates evidence from preclinical and clinical work on the onset, progression and outcome of axonal degeneration in CIPN. We review likely triggers of axonal degeneration in CIPN and highlight evidence of molecular pathways involved in axonal degeneration and their relevance to CIPN, including SARM1-mediated axon degeneration pathway. We identify potential clinical markers of axonal dysfunction to provide early identification of toxicity as well as present potential treatment strategies to intervene in axonal degeneration pathways. A greater understanding of axonal degeneration processes in CIPN will provide important information regarding the development and progression of axonal dysfunction more broadly and will hopefully assist in the development of successful interventions for CIPN and other neurodegenerative disorders.

Morphofunctional characterisation of axonal damage in different rat models of chemotherapy‐induced peripheral neurotoxicity: The role of nerve excitability testing

“…One of the major issues in designing a preventive clinical trial in CIPN is enrolling patients who will actually develop peripheral neuropathy, since not all patients will experience CIPN and, even if neurotoxicity ensues, its severity can vary. 4,7,10,28 We already proposed the longitudinal monitoring of the dorsal sural nerve at mid-treatment to detect patients at higher risk to develop neuropathy in a clinical setting, 6 but it would be far more valuable to have a tool that even more precociously can detect changes predictive of axonal damage, as NET was demonstrated to be doing in our preclinical proof-of-concept study. Furthermore, differently from serum biomarkers such as neurofilament light chain (NfL) levels, 8 Thus, it could be suggested that NET should be further explored as a precious link between bench and bedside for research purposes: in fact, at bench side, all hypotheses just indirectly inferred via NET on axonal damage can be directly confirmed via histopathology and biomolecular techniques.…”

“…19,22,31,38 In part, this unmet clinical and scientific need is due to an incomplete understanding of axonal damage mechanisms related to different anticancer drugs. 28 Therefore, it is crucial to have robust preclinical models addressing pathogenetic mechanisms. 15 In this regard in vivo models are pivotal and it is mandatory to use translational methods to promptly transfer data from bench to bedside and vice versa; nerve conduction studies (NCS) are quite a relevant option since they can be similarly performed at a preclinical and clinical level in CIPN.…”

“…In part, this unmet clinical and scientific need is due to an incomplete understanding of axonal damage mechanisms related to different anticancer drugs 28 . Therefore, it is crucial to have robust preclinical models addressing pathogenetic mechanisms 15 .…”

“…In CIPN NET was little explored apart from the OHP‐related setting; only a small study on a clinical cohort was published suggesting that NET can detect early changes due to antitubulinic agent 29 . To further explore NET exploitability to test CIPN pathogenesis, we therefore used NET in two different robust CIPN models, one related to platinum compounds, OHP, and the other to an antitubulinic agent, paclitaxel (PTX), whose neurotoxic patterns are quite different: platinum compounds first target dorsal root ganglia (DRG) neurons and cause a mild sensory axonal neuronopathy, whereas, PTX, thanks to its effects on microtubules, exerts a relevant damage in axons leading to a moderate‐severe sensory‐motor axonal polyneuropathy 7,28 . Our aim was to explore NET use in CIPN setting to exploit its full potential in monitoring early alterations related to different mechanisms underlying axonal damage.…”

Incidence and risk factors for developing chemotherapy‐induced neuropathic pain in 500 cancer patients: A file‐based observational study

“…Different antineoplastic agents target distinct components of the PNS including apoptosis of DRG neuronal cell bodies, changes in axonal transport pathways, mitochondrial dysfunction, and abnormalities in Ca 2+ regulation systems as well as axonal membrane ion channels. 12,13 Accordingly, its clinical features are dependent on the type of the agent involved, ranging from pure sensory axonal to sensory-motor neuropathies, with or without pain and autonomic impairment. 14 Its clinical phenotype is mainly characterized by paresthesias and dysesthesias in peripheral limbs, numbness, ataxia, tingling, decreased sense of vibration and impaired deep tendon reflexes.…”