Oral administration of Cystine and Theanine ameliorates oxaliplatin-induced chronic peripheral neuropathy in rodents

Takehiro Kawashiri,Nobuaki Egashira,Takao Shimazoe,Daisuke Kobayashi,Takashi Tsuchiya

doi:10.1038/s41598-020-69674-9

Takehiro Kawashiri, Nobuaki Egashira + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-69674-9

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Abstract

Oxaliplatin frequently causes severe peripheral neuropathy as a dose-limiting toxicity. However, this toxicity lacks a strategy for prevention. Cystine/Theanine is a supplement, which includes precursors for the biosynthesis of glutathione. In this study, we investigated the effects of Cystine/Theanine on oxaliplatin-induced peripheral neuropathy using an in vivo model. Repeated injection of oxaliplatin (4 mg/kg intraperitoneally twice a week for 2 weeks) caused mechanical allodynia, cold hyperalgesia and axonal degeneration of the sciatic nerve in rats. Mechanical allodynia and axonal degeneration, but not cold hyperalgesia, were ameliorated by daily co-administration of Cystine [200 mg/kg orally (p.o.)] and Theanine (80 mg/kg p.o.). Moreover, co-administration of Cystine and Theanine to rats significantly increased the glutathione level in the sciatic nerve compared with the oxaliplatin group. Furthermore, Cystine and Theanine did not attenuate the tumour cytotoxicity of oxaliplatin in C-26 tumour cell-bearing mice. These findings suggest that Cystine and Theanine may be beneficial for preventing oxaliplatin-induced peripheral neuropathy.

Highlights

Oxaliplatin frequently causes severe peripheral neuropathy as a dose-limiting toxicity
Effect of Cystine/Theanine on mechanical allodynia induced by oxaliplatin in rats
A previous study indicated there is a distinct difference between metabolites responsible for acute and chronic neuropathy caused by oxaliplatin; oxalate and platinum metabolites are involved in cold hyperalgesia and mechanical allodynia, respectively[20]

Summary

Introduction

Oxaliplatin frequently causes severe peripheral neuropathy as a dose-limiting toxicity. Repeated injection of oxaliplatin (4 mg/kg intraperitoneally twice a week for 2 weeks) caused mechanical allodynia, cold hyperalgesia and axonal degeneration of the sciatic nerve in rats. Cystine and Theanine did not attenuate the tumour cytotoxicity of oxaliplatin in C-26 tumour cell-bearing mice These findings suggest that Cystine and Theanine may be beneficial for preventing oxaliplatin-induced peripheral neuropathy. Oxaliplatin, a platinum-based chemotherapeutic agent, is widely used for the standard treatment of colorectal, gastric, and pancreatic cancers, frequently causes severe peripheral neuropathy. Acute neuropathy such as cold-related paraesthesia in hands, feet and the perioral region manifests within hours to days after oxaliplatin infusion. Glutathione has reduced oxaliplatin-induced peripheral neurotoxicity in clinical s tudies[18,19]

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