title: The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.
abstract: 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.
authors: Neuroimmunology Laboratory, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America; Department of Integrative Medicine and Neurobiology, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China.
authors: Qi-Liang
authors: QL
authors: Mao-Ying
authors: Neuroimmunology Laboratory, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors: Annemieke
authors: A
authors: Kavelaars
authors: Neuroimmunology Laboratory, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors: Karen
authors: K
authors: Krukowski
authors: Neuroimmunology Laboratory, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors: Xiao-Jiao
authors: XJ
authors: Huo
authors: Neuroimmunology Laboratory, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors: Wenjun
authors: W
authors: Zhou
authors: School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas, United States of America.
authors: Theodore J
authors: TJ
authors: Price
authors: Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors: Charles
authors: C
authors: Cleeland
authors: Neuroimmunology Laboratory, Department of Symptom Research, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors: Cobi J
authors: CJ
authors: Heijnen
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000009:adverse effects; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology; D009437:Neuralgia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D017239:Paclitaxel / Q000009:adverse effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D020011:Protective Agents; D008687:Metformin; D017239:Paclitaxel; D002945:Cisplatin