Chemotherapy-induced peripheral neuropathy is promoted by enhanced spinal insulin-like growth factor-1 levels via astrocyte-dependent mechanisms.

Abstract

BACKGROUND:

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intractable complication in chemotherapy-receiving patients. Insulin-like growth factor-1 (IGF-1) is a popular neurotrophin with various functions, such as maintaining neuronal survival and synaptic functioning in the central nervous system. Therefore, we hypothesized that the IGF-1 signaling pathway could be a candidate target for treating CIPN.

METHODS:

We established the CIPN model by injecting mice intraperitoneally with oxaliplatin and assessed IGF-1 protein expression, its receptor IGF1R, phospho-IGF1R (p-IGF1R), interleukin-17A (IL-17A), tumor necrosis factor-α (TNF-α), and calcitonin gene-related peptide (CGRP) in the lumbar spinal cord with Western blot and immunofluorescence. To examine the effect of IGF-1 signaling on CIPN, we injected mice intrathecally or intraperitoneally with mouse recombinant IGF-1 (rIGF-1).

RESULTS:

IGF-1 protein expression decreased significantly in the spinal cord on D3 and D10 (the 3rd and 10th days after beginning oxaliplatin chemotherapy) and was co-localized with astrocytes primarily in the lumbar spinal cord, whereas IGF1R was predominantly expressed on neurons. Both intrathecally- and intraperitoneally-administered rIGF-1 relieved the chemotherapy-induced pain-like behavior and reduced IL-17A, TNF-α, and CGRP protein expressions in the spinal cord.

CONCLUSION:

Our results indicate a vital role for IGF-1 signaling in CIPN. Targeting IGF-1 signaling could be a potent therapeutic strategy for treating CIPN in clinical settings.

• Authors: Yue Le, Xin Chen, Long Wang, Wan-You He, Jian He, Qing-Ming Xiong, Yun-Hua Wang, Lei Zhang, Xue-Qin Zheng, Han-Bing Wang
• Journal: Brain research bulletin (Brain Res Bull) Vol. 175 Pg. 205-212 (10 2021) ISSN: 1873-2747 [Electronic] United States
• PMID: 34333050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cytokines
• insulin-like growth factor-1, mouse
• Oxaliplatin
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1

Topics

• Animals
• Antineoplastic Agents (toxicity)
• Astrocytes (drug effects, metabolism)
• Cytokines (metabolism)
• Injections, Spinal
• Insulin-Like Growth Factor I (biosynthesis, pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Neurons
• Oxaliplatin (toxicity)
• Pain (psychology)
• Peripheral Nervous System Diseases (chemically induced, psychology)
• Receptor, IGF Type 1 (drug effects)
• Signal Transduction (drug effects)
• Spinal Cord (metabolism)