Efficacy of Goshajinkigan for prophylaxis against oxaliplatin-induced peripheral neuropathy.

Abstract

576 Background: Oxaliplatin-induced peripheral neuropathy (OPN) is often observed and is the most frequent dose-limiting toxicity. However, there is no effective therapeutic option for preventing OPN. Goshajinkigan (GJG), a traditional Japanese herbal medicine, has widely been used for disease-assessed neuropathy in Japan. Recently, the preventive effect of GJG against OPN in a placebo-controlled double-blind randomized phase II study was reported (Kono T et al., Cancer Chemother Pharmacol. 2013, 72,1283-90). However, the precise mechanisms underlying preventive effect of GJG are unknown. Methods: To be established the OPN rat model, oxaliplatin (4 mg/kg) was injected intraperitoneally twice weekly for 8 weeks in rats. Animals were treated with oral administration of GJG (0.3, 1.0 g/kg) five times a week for 8 weeks. We performed behavioral tests (acetone test and hot plate test) and pathological examination of neuronal tissue using the OPN rat model. We carried out pharmacokinetic study of GJG and searched for active ingredients in GJG in order to explore the mechanism of GJG. Results: The rats injected with oxaliplatin for a long-term showed both cold hypersensitivity and heat hyposensitivity. Co-administration of GJG ameliorated OPN in the rat. In light and electron microscopic study, scattered axonal damages in sciatic nerve of oxaliplatin groups were observed, which were substantially suppressed by GJG. Pharmacokinetic study revealed that considerable neuroprotective and analgesic ingredients were detected after oral administration of GJG in rat plasma. Some ingredients in GJG significantly suppressed oxidative stress caused by oxaliplatin in the experiment using neuronal cells. Conclusions: Oxaliplatin-induced chronic neuropathy symptoms are similar to human symptoms caused by long-term oxaliplatin administration. Oral administration of GJG in rat substantially diminished OPN, and promises to provide an effective and convenient treatment at risk of developing peripheral neuropathy in oxaliplatin-treated patients.