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.

Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin

“…In addition, metformin is capable of attenuating hyperexcitability in sensory neurons that were exposed to cytokines and growth factors which has been associated with chemotherapy-induced neuropathic pain. In an in vivo study, metformin protects against chemotherapy induced neuropathic pain in a mouse model (Mao-Ying et al, 2014). All those findings show the neuroprotective effect of metformin on sensation and raise its potential in alleviating neuropathic pain in diabetes mellitus.…”

Pioglitazone Inhibits the Development of Hyperalgesia and Sensitization of Spinal Nociresponsive Neurons in Type 2 Diabetes

“…Finally, a multiple drug strategy, such as coadministration of pioglitazone with canagliflozin 105 or geraniol 34 might reduce diabetes without the adverse effects of adipocyte differentiation, fat deposition, and weight gain associated with pioglitazone-only treatment. PDN patients may also benefit from other diabetic drugs such as metformin, which reduces peripheral neuropathic pain 57 and PDN in STZ rats 7, 54 , as well as decreases hyperglycemia, HbA1c, and MG in patients with type 2 diabetes 41 . Future clinical studies could investigate whether the above treatments or other PPARγ-directed therapies alleviate both hyperglycemia and neuropathic pain, as simultaneous inhibition is necessary to maximize quality of life in type 2 diabetic patients.…”

Translational Control Mechanisms in Persistent Pain

“…Metformin is thought to exert its effects by activating AMPK and inhibiting mRNA translation via TSC2, Raptor, and BRAF; however, several AMPK-independent actions of metformin have also been documented [63]. Metformin showed dramatic effects in mouse and rat models of neuropathic and inflammatory pain, leading to an alleviation of thermal and mechanical hypersensitivity, and promoting neuroprotection in models of chemotherapy-induced peripheral neuropathic pain [6,65]. A key feature of metformin is its disease-modifying properties in neuropathic pain models, wherein metformin treatment leads to sustained pain relief several months after cessation of treatment.…”