Ergothioneine ameliorates oxaliplatin-induced peripheral neuropathy in rats

Abstract

AimsOxaliplatin (l-OHP) is a key drug in therapeutic regimens for metastatic or advanced-stage colorectal cancer, but causes peripheral neuropathy as a dose-limiting adverse effect. It is reported that this peripheral neuropathy results from l-OHP accumulation in dorsal root ganglion (DRG) neurons, and that one of the transporters responsible for the accumulation in DRG neurons is organic cation transporter novel (OCTN) 1. Here, we examined whether co-administration of ergothioneine, a substrate/inhibitor of OCTN1, with l-OHP could prevent this peripheral neuropathy. Main methodsl-OHP (4 mg/kg, i.p., twice/week, for 6 weeks) and ergothioneine or l-carnitine (1.5 or 15 mg/kg, i.v., twice per l-OHP administration) were administered to rats, and tissue/cellular platinum concentrations and peripheral neuropathy were determined. Expression of transporters in DRG neuronal cells was evaluated by real-time PCR and immunocytochemistry. Key findingsOn administration of l-OHP to rats, it accumulated in DRG neurons and their mitochondria, while negligible accumulation was found in Schwann cells. Expression of OCTN1 was observed in DRG neurons, especially in small- and medium-sized ones, which are responsible for the nociceptive response. In rats repeatedly administered l-OHP, co-administration of ergothioneine (15 mg/kg), but not l-carnitine, a substrate/inhibitor of OCTN2, decreased l-OHP accumulation in DRGs and development of the mechanical allodynia. SignificanceThese results indicated that l-OHP-induced peripheral neuropathy was ameliorated by co-administration of ergothioneine, at least in part, via a decrease in its accumulation in DRG neurons. Plant diets contain ergothioneine, and thus their consumption might offer relief to patients suffering from l-OHP-induced peripheral neuropathy.