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Review
. 2021 Jun 11:8:693133.
doi: 10.3389/fmolb.2021.693133. eCollection 2021.

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

Maryam Omran  1 , Elizabeth K Belcher  1 , Nimish A Mohile  1 , Shelli R Kesler  2 , Michelle C Janelsins  1 , Andrea G Hohmann  3 , Ian R Kleckner  1
Affiliations
Review

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

Maryam Omran et al. Front Mol Biosci. .

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating, and dose-limiting side effect of many chemotherapy regimens yet has limited treatments due to incomplete knowledge of its pathophysiology. Research on the pathophysiology of CIPN has focused on peripheral nerves because CIPN symptoms are felt in the hands and feet. However, better understanding the role of the brain in CIPN may accelerate understanding, diagnosing, and treating CIPN. The goals of this review are to (1) investigate the role of the brain in CIPN, and (2) use this knowledge to inform future research and treatment of CIPN. We identified 16 papers using brain interventions in animal models of CIPN and five papers using brain imaging in humans or monkeys with CIPN. These studies suggest that CIPN is partly caused by (1) brain hyperactivity, (2) reduced GABAergic inhibition, (3) neuroinflammation, and (4) overactivation of GPCR/MAPK pathways. These four features were observed in several brain regions including the thalamus, periaqueductal gray, anterior cingulate cortex, somatosensory cortex, and insula. We discuss how to leverage this knowledge for future preclinical research, clinical research, and brain-based treatments for CIPN.

Keywords: brain; chemotherapy; clinical; neuropathy; translational.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic of our hypothesis that CIPN symptoms are caused by (1) brain sensitization and compensation due to peripheral and spinal nerve damage and dysfunction, which is shown in the red box and is the focus of our novel review, plus two more well-studied phenomena: (2) spinal sensitization and compensation, and (3) peripheral nerve damage. Our hypothesis does not depend on whether chemotherapy enters the brain (green dashed arrows) for changes in the brain to contribute to CIPN symptoms. Image adapted from innerbody.com.
FIGURE 2
FIGURE 2
Conceptual model for the role of the brain in CIPN based on the evidence reviewed herein. The red text indicates brain factors that cause or are correlated with CIPN. The blue text indicates brain interventions shown to treat or reduce CIPN via the experimental studies (first author provided in parentheses; all studies reviewed in Table 3). Lines ending in a circle indicate blocking or reducing the target whereas lines ending in an arrow indicate activating or increasing the target. The key brain regions studied and implicated in our review include the periaqueductal gray (PAG), thalamus, anterior cingulate cortex (ACC), secondary somatosensory cortex (S2), and insula.
See this image and copyright information in PMC

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