Metformin protects from oxaliplatin induced peripheral neuropathy in rats

N.W Martinez,A Sánchez,P Diaz,R Broekhuizen,J Godoy,S Mondaca,A Catenaccio,P Macanas,B Nervi,M Calvo,F.A Court

doi:10.1016/j.ynpai.2020.100048

Abstract

Oxaliplatin is a commonly used drug to treat cancer, extending the rate of disease-free survival by 20% in colorectal cancer. However, oxaliplatin induces a disabling form of neuropathy resulting in more than 60% of patients having to reduce or discontinue oxaliplatin, negatively impacting their chance of survival. Oxaliplatin-induced neuropathies are accompanied by degeneration of sensory fibers in the epidermis and hyperexcitability of sensory neurons. These morphological and functional changes have been associated with sensory symptoms such as dysesthesia, paresthesia and mechanical and cold allodynia. Various strategies have been proposed to prevent or treat oxaliplatin-induced neuropathies without success. The anti-diabetic drug metformin has been recently shown to exert neuroprotection in other chemotherapy-induced neuropathies, so here we aimed to test if metformin can prevent the development of oxaliplatin-induced neuropathy in a rat model of this condition. Animals treated with oxaliplatin developed significant intraepidermal fiber degeneration, a mild gliosis in the spinal cord, and mechanical and cold hyperalgesia. The concomitant use of metformin prevented degeneration of intraepidermal fibers, gliosis, and the altered sensitivity. Our evidence further supports metformin as a new approach to prevent oxaliplatin-induced neuropathy with a potential important clinical impact.

Highlights

Oxaliplatin, a platinum derivative, is commonly indicated for the treatment of solid tumors such as colorectal cancer, the third most common cancer in men and the second in women worldwide (The Lancet 2018)
In this study we show that metformin, a widely used antidiabetic drug, protects axonal degeneration in vitro and in a rat model of oxaliplatin induced neuropathy
Rats exposed to oxaliplatin developed degeneration of intraepidermal fibers, activation of astrocytes in the spinal cord and mechanical and cold hyperalgesia, all of which were prevented by metformin co-administration

Summary

Introduction

Oxaliplatin, a platinum derivative, is commonly indicated for the treatment of solid tumors such as colorectal cancer, the third most common cancer in men and the second in women worldwide (The Lancet 2018) In this disease, oxaliplatin has shown clinically important benefits in the adjuvant setting and for metastatic disease (de Gramont et al, 2000, Andre et al, 2015). OIPN is still unpredictable, while symptoms may resolve after chemotherapy is discontinued, they can continue for years It is associated with sensory and motor axon loss that can be detected by electrophysiology, or by reduction in intraepidermal fibre density in a length dependent pattern (Burakgazi et al, 2011).

Objectives

Methods

Results

Conclusion