Cargando…

The Anti-Diabetic Drug Metformin Protects against Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model

Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used...

Descripción completa

Detalles Bibliográficos
Autores principales: Mao-Ying, Qi-Liang, Kavelaars, Annemieke, Krukowski, Karen, Huo, Xiao-Jiao, Zhou, Wenjun, Price, Theodore J., Cleeland, Charles, Heijnen, Cobi J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067328/
https://www.ncbi.nlm.nih.gov/pubmed/24955774
http://dx.doi.org/10.1371/journal.pone.0100701
_version_ 1782322275568058368
author Mao-Ying, Qi-Liang
Kavelaars, Annemieke
Krukowski, Karen
Huo, Xiao-Jiao
Zhou, Wenjun
Price, Theodore J.
Cleeland, Charles
Heijnen, Cobi J.
author_facet Mao-Ying, Qi-Liang
Kavelaars, Annemieke
Krukowski, Karen
Huo, Xiao-Jiao
Zhou, Wenjun
Price, Theodore J.
Cleeland, Charles
Heijnen, Cobi J.
author_sort Mao-Ying, Qi-Liang
collection PubMed
description Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs) in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.
format Online
Article
Text
id pubmed-4067328
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-40673282014-06-25 The Anti-Diabetic Drug Metformin Protects against Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model Mao-Ying, Qi-Liang Kavelaars, Annemieke Krukowski, Karen Huo, Xiao-Jiao Zhou, Wenjun Price, Theodore J. Cleeland, Charles Heijnen, Cobi J. PLoS One Research Article Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs) in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved. Public Library of Science 2014-06-23 /pmc/articles/PMC4067328/ /pubmed/24955774 http://dx.doi.org/10.1371/journal.pone.0100701 Text en © 2014 Mao-Ying et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Mao-Ying, Qi-Liang
Kavelaars, Annemieke
Krukowski, Karen
Huo, Xiao-Jiao
Zhou, Wenjun
Price, Theodore J.
Cleeland, Charles
Heijnen, Cobi J.
The Anti-Diabetic Drug Metformin Protects against Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model
title The Anti-Diabetic Drug Metformin Protects against Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model
title_full The Anti-Diabetic Drug Metformin Protects against Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model
title_fullStr The Anti-Diabetic Drug Metformin Protects against Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model
title_full_unstemmed The Anti-Diabetic Drug Metformin Protects against Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model
title_short The Anti-Diabetic Drug Metformin Protects against Chemotherapy-Induced Peripheral Neuropathy in a Mouse Model
title_sort anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067328/
https://www.ncbi.nlm.nih.gov/pubmed/24955774
http://dx.doi.org/10.1371/journal.pone.0100701
work_keys_str_mv AT maoyingqiliang theantidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT kavelaarsannemieke theantidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT krukowskikaren theantidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT huoxiaojiao theantidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT zhouwenjun theantidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT pricetheodorej theantidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT cleelandcharles theantidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT heijnencobij theantidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT maoyingqiliang antidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT kavelaarsannemieke antidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT krukowskikaren antidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT huoxiaojiao antidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT zhouwenjun antidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT pricetheodorej antidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT cleelandcharles antidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel
AT heijnencobij antidiabeticdrugmetforminprotectsagainstchemotherapyinducedperipheralneuropathyinamousemodel