Goshajinkigan, a Traditional Japanese Medicine, Prevents Oxaliplatin-Induced Acute Peripheral Neuropathy by Suppressing Functional Alteration of TRP Channels in Rat

Abstract

Abstract. The acute peripheral neuropathy induced by oxaliplatin treatment occurs very frequently and is aggravated by exposure to cold. Goshajinkigan (GJG), a traditional Japanese (kampo) medicine, was recently shown to be effective against oxaliplatin-induced acute neuropathy. However, because the effects of GJG and its mechanism in relation to those of its ingredients and its mechanism are not well understood, we examined the effects of GJG on acute neuropathy. Further, we investigated whether GJG affects the functions and gene expressions of transient receptor potential (TRP) channels using a rat model of oxaliplatin-induced neuropathy. Administration of oxaliplatin increased withdrawal responses from cold stimulation, and GJG or calcium gluconate/ magnesium sulfate significantly inhibited the oxaliplatin-induced cold hypersensitivity. Application of menthol, a TRPA1/TRPM8 agonist, or allyl isothiocyanate (AITC), a selective TRPA1 agonist, to the hind paw of oxaliplatin-treated rats enhanced the nocifensive behaviors evoked by each agonist, whereas oxaliplatin had no significant effect on nocifensive behaviors evoked by capsaicin, a TRPV1 agonist. GJG treatment reduced menthol-or AITC-evoked withdrawal responses potentiated by oxaliplatin. Furthermore, GJG suppressed the increase of TRPA1 and TRPM8 mRNA expression induced by oxaliplatin in dorsal root ganglia. These findings suggest that GJG prevented oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels, especially TRPA1 and TRPM8.

Low-level laser therapy alleviates mechanical and cold allodynia induced by oxaliplatin administration in rats

“…In the present study, oxaliplatin caused cold and mechanical allodynia in the early phase, consistent with previous reports [10,17,31]. The repeated application of LLLT reduced the oxaliplatin-induced cold and mechanical allodynic responses in the von Frey test, acetone test, cold-water (5°C) limbimmersion test, as well as menthol-evoked nocifensive behavior in rats.…”

“…Accumulating evidence from recent studies indicates that TRPM8, which is activated by cooling temperatures and agents such as menthol, is responsible for oxaliplatininduced cold hypersensitivity [9,10,31,38]. In this study, based on Western blot results, administration of oxaliplatin increased the protein levels of TRPM8 in DRG.…”

“…There are numerous reports on the use of pharmacologic agents to prevent or treat this painful neuropathy in humans [32][33][34] and rats [27,31,35]. Furthermore, the addition of dietary nutritional therapy and some herbal preparations may also prevent or relieve the oxaliplatin-induced cold hyperalgesia and mechanical allodynia without affecting antitumour activity of oxaliplatin [18,[36][37][38].…”

“…Menthol, a TRPM8 agonist, evokes a cooling sensation when applied to the skin [31]. The duration of menthol-induced nocifensive behaviors (licking, flinching, lifting, and backward walking of the stimulated hind paw) was measured for 5 min.…”

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

“…An increasing number of studies report the involvement of TRP channels including TRPA1, TRPM8, TRPV1, and TRPV4 in CIPN [112][113][114][115]. Recent studies found that Jesengsingi-Hwan prevents oxaliplatin-induced peripheral neuropathy through the functional alteration in TRPA1 and TRPM8 [116] and can reduce paclitaxel-induced peripheral neuropathy by suppressing TRPV4 expression [117]. Moreover, the TRPV1-mediated anti-cancer effects of cannabidiol have been reported in multiple cancer cell lines, including breast [118], lung [119,120], and colon [121].…”