67. The AMP-kinase inhibitor metformin inhibits chemotherapy-induced peripheral neuropathy

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. There are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin inhibits pathological pain following nerve injury in mice and rats. We tested the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits in mice. Mice were treated with cisplatin together with metformin or saline. Co-administration of metformin almost completely prevented the cisplatin- and paclitaxel-induced mechanical allodynia. Cisplatin decreased the time to detect an adhesive patch on the hind paw, a novel indicator of sensory deficits. Reduced sensory function was prevented by co-administration of metformin. Moreover, metformin prevented cisplatin-induced loss of IENFs in the hind paw. In the spinal cord, metformin treatment altered glial activation, indicating a contribution of regulation of neuroinflammation to the protective effect. In conclusion, metformin protects against pain and loss of sensory function in a mouse model of CIPN. The mechanism involves reduced peripheral nerve damage and changes in neuroinflammation, strongly suggesting that metformin exerts a neuroprotective effect. 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.