Preventive effect of oral goshajinkigan on chronic oxaliplatin-induced hypoesthesia in rats

Abstract

Oxaliplatin, a widely used chemotherapeutic agent, induces peripheral neuropathy that manifests itself as two distinct phases: acute cold hyperesthesia and chronic peripheral hypoesthesia/dysesthesia. The latter is a serious dose-limiting side effect that can often lead to withdrawal of treatment. We have developed a rat model expressing both phases and used the model to investigate the action of goshajinkigan (GJG), a traditional Japanese herbal medicine, which was reported to ameliorate oxaliplatin-induced neuropathy in a placebo-controlled double-blind randomized phase II study. In this study, neuropathy was induced by injection of oxaliplatin twice weekly for 8 wks. The maximum level of cold hyperesthesia was observed at 4 wks with heat hypoesthesia developing later. Microscopy studies revealed atrophy of axons of myelinated sciatic nerve fibers in oxaliplatin-treated rats at 8 wks. Co-administration of GJG ameliorated both abnormal sensations as well as histological damage to the sciatic nerve. A pharmacokinetic study revealed numerous neuroprotective components of GJG that are rapidly absorbed into the blood. GJG and some of its components attenuated the generation of oxaliplatin-induced reactive oxygen species, which is a possible mechanism of oxaliplatin-induced neurotoxicity. The present study provides a useful animal model for oxaliplatin-induced neurotoxicity as well as a promising prophylactic agent.

Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy

“…One such pharmacological herbal mixture, GJG, has been shown in animal studies and small clinical studies to prevent CIPN [Schroder, et al 2013, Tawata, et al 1994]. GJG alleviates paclitaxel induced hyperalgesia by preventing degeneration of the ganglion cells and suppressing TRPV4 expression [Matsumura, et al 2014], bortezomib-induced mechanical allodynia through the kappa opioid receptor [Higuchi, et al 2015] and oxaliplatin through attenuation of the generation of oxaliplatin-induced reactive oxygen species [Kono, et al 2015]. Our research has demonstrated the potentiality of GJG to protect human iPSC-derived cortical neurons against paclitaxel-induced neuropathy without causing decreased sensitivity of particular cancer cells (i.e.…”

Therapeutic Effects of Phytochemicals and Medicinal Herbs on Chemotherapy-Induced Peripheral Neuropathy

“…Kono et al examined a preventive effect of Jesengsingi-Hwan on chronic oxaliplatin-induced hypoesthesia in rats. Oral administration of Jesengsingi-Hwan (0.3 or 1.0 g/kg, 5 times a week for 8 weeks) ameliorated abnormal sensations and histological damage to the sciatic nerve [42]. In a retrospective clinical study, Kono et al examined the benefits of Jesengsingi-Hwan on oxaliplatin treatment involved in peripheral neuropathy.…”

“…Reduces peripheral neuropathy without influence on anti-cancer potency Ameliorates abnormal sensations and histological damage to the sciatic nerve [41,42] Paclitaxel in mice Inhibits mechanical allodynia [43] Oxaliplatin in a placebo-controlled double-blind randomized study Delays onset of grade 2 or greater peripheral neurotoxicity without impairing FOLFOX efficacy with an acceptable safety margin [44,45] Prevents exacerbation of peripheral neuropathy [46,47] A clinical trial enrolling 82 patients Reduces peripheral neuropathy [48] …”

An effective therapeutic approach for oxaliplatin-induced peripheral neuropathy using a combination therapy with goshajinkigan and bushi

“…2C-F). In addition, Kono et al reported a morphological analysis demonstrated that oxaliplatin causes the atrophy of axons containing myelinated nerve fibers but not non-myelinated nerve fibers in the sciatic nerves in rats and that this effect was ameliorated by GJG 17 . The simplest interpretation of these findings is that an increase in the sensitivity of either Aδ- or Aβ-fibers or both is involved in the induction of mechanical allodynia and that GJG, acting on these sensory fibers, inhibits their sensitization.…”