Neuroprotective effect of alogliptin on oxaliplatin-induced peripheral neuropathy in vivo and in vitro

Nao Shigematsu,Shiori Hiromoto,Nobuaki Egashira,Daisuke Kobayashi,Keisuke Mine,Takao Shimazoe,Mayako Uchida,Shiori Shimizu,Takehiro Kawashiri

doi:10.1038/s41598-020-62738-w

Abstract

Oxaliplatin is a platinum-based antineoplastic drug commonly used for treating colorectal, gastric, and pancreatic cancer. However, it frequently causes peripheral neuropathy as dose-limiting toxicity and is lacking a strategy for prevention. Alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, is an oral antidiabetic drug. Previous studies have shown that DPP-4 inhibitors have pleiotropic effects, including neuroprotection. In this study, we investigated the effects of alogliptin on oxaliplatin-induced peripheral neuropathy using in vitro and in vivo models. In PC12 cells, alogliptin attenuated neurite disorders induced by oxaliplatin and cisplatin. The repeated injection of oxaliplatin caused mechanical allodynia and axonal degeneration of the sciatic nerve in rats. These neuropathies were ameliorated by co-administration of alogliptin. Moreover, alogliptin did not attenuate tumor cytotoxicity of oxaliplatin in the cultured colon, gastric, or pancreatic cancer cell lines and tumor-bearing mice. These findings suggest that alogliptin may be beneficial for preventing oxaliplatin-induced peripheral neuropathy.

Highlights

Oxaliplatin is a platinum-based antineoplastic drug commonly used for treating colorectal, gastric, and pancreatic cancer
According to the clinical practice guideline established by the American Society of Clinical Oncology in 2014, no agents have yet to be recommended for the prevention of chemotherapy-induced peripheral neuropathy[11]
Effect of alogliptin on neurodegeneration induced by chemotherapeutic agents in PC12 cells

Summary

Introduction

Oxaliplatin is a platinum-based antineoplastic drug commonly used for treating colorectal, gastric, and pancreatic cancer It frequently causes peripheral neuropathy as dose-limiting toxicity and is lacking a strategy for prevention. Chronic neurotoxicity is considered to be caused by morphological changes in neurons, such as axon degeneration, neuronal cell body damage, and myelin disorder[7,8,9] These neuropathies remain a significant clinical problem in chemotherapy with oxaliplatin as they impact the quality of life and can lead to drug reduction or discontinuation. Alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, is clinically used for the treatment of type 2 diabetes mellitus It lowers the blood glucose level mainly by preventing the inactivation of glucagon-like peptide-1 (GLP-1). We sought to evaluate the effect of alogliptin on oxaliplatin-induced peripheral neuropathy using in vitro and in vivo models

Methods

Results

Conclusion