Mechanisms underlying select chemotherapeutic-agent-induced neuroinflammation and subsequent neurodegeneration

Abstract

This review demonstrates the importance of uncovering the mechanisms that underlie chemotherapy-induced neuroinflammation. It builds upon the well-established connection between chemotherapeutic-agents and neurotoxicity along with widespread peripheral toxicities. This article summarises the major studies which have linked chemotherapyinduced neurodegeneration with direct evidence of neuroinflammation. Cancer and chemotherapy-related adverse effects impact a large proportion of the population. A better understanding of the link between chemotherapy, neurotoxicity and specifically the mechanisms of neuroinflammation, will allow the development of strategies to improve the management of side effects, and overall to reduce the burden on cancer patients receiving chemotherapy. This review has developed a summary schematic of the relationship between different chemotherapeutic agents and inflammatory markers within the central nervous 1 Denotes equal contribution to work 2 system and links this correlation with some major ailments associated with chemotherapy use.

Review of the Role of the Brain in Chemotherapy-Induced Peripheral Neuropathy

“…This hypothetical compensation in the brain might have implications for traditional perspectives of the role of the brain in pain, such as how neurotoxic chemotherapy might cause a reduction in descending inhibition of pain (e.g., according to Gate Control Theory Melzack and Wall, 1965). For completeness, these hypothetical changes in the brain would be concurrent with other effects of chemotherapy such as neuroinflammation (McLeary et al, 2019), which sensitizes neurons and causes hyperactivity (Vezzani and Viviani, 2015).…”

Systemic loss of Sarm1 protects Schwann cells from chemotoxicity by delaying axon degeneration

“…Many chemotherapeutic agents invariably cause peripheral neurotoxicity, leading to permanent neuronal dysfunction [75][76][77][78][79] . Under conditions of denervation, Schwann cells become strongly susceptible to chemotoxicity 80 .…”

Life after Cell Death—Survival and Survivorship Following Chemotherapy

“…Reciprocal and multidirectional effects of cell death, vascular activation, tumour-secreted factors, and therapy-induced responses, such as senescence, promote a widespread state of inflammation [134]. The effects of chemotherapy on intestinal epithelium, an inevitable target due to its high turnover rate, results in massive endotoxin release from gut microflora into circulation [135]. Inflammatory mediators, in turn, further contribute to microvascular remodelling, activation and increased permeability, perpetuating the cycle of vascular pathology, cardiovascular disease and oedema [136], as well as affecting the response to treatment [137] and potential for relapse [99].…”

“…Memory loss, disorganized thoughts, difficulty concentrating, and declines in recall and processing speed are seen in up to 80% of chemotherapy patients. While generally 35% of these patients report symptoms for years after completion of treatment [135], the proportion of breast cancer patients reporting long-term effects is almost twice that, nearing 60%, particularly in those treated with doxorubicin and/or cyclophosphamide [131,138]. A recent study has shown that these effects persist for 20 years after treatment, and those with lower cognitive function had associated higher levels of inflammatory markers [140].…”

“…A recent study has shown that these effects persist for 20 years after treatment, and those with lower cognitive function had associated higher levels of inflammatory markers [140]. These side effects correlate with structural changes in the brain, including a significant decrease in areas of grey and white matter [135,141]. In mice treated with paclitaxel, activation and time to resolution of circulating cytokines (CXCL1, Il-1b, and TNF-α) showed a transient pattern, with CXCL1 persisting for longer [134].…”