Gosha-jinki-gan reduced oxaliplatin-induced hypersensitivity to cold sensation and its effect would be related to suppression of the expression of TRPM8 and TRPA1 in rats.
Peripheral neuropathy is a common side effect of the chemotherapeutic agent oxaliplatin (Oxp), and is associated with hypersensitivity to cold sensation in the acute stage. Recently, gosha-jinki-gan (GJG), a Japanese herbal medicine, was reported to improve Oxp-induced cold hypersensitivity. However, the mechanism for this effect was not elucidated. We hypothesized that the effect of GJG on Oxp-induced cold hypersensitivity may be associated with the expression of the transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) channels, which are cold-gated ion channels. To assess this hypothesis, we examined alteration of the withdrawal response to cold stimulation following coadministration of GJG and Oxp in rats, and the relationship between this altered withdrawal response and the expression of TRPM8 and TRPA1 mRNA in the dorsal root ganglia (DRG). Assessment of cold hypersensitivity was performed at 4 and 10°C using a cold plate. Compared with Oxp administration alone, coadministration of GJG (oral dose: 1 g/kg/day for 12 days) and Oxp (intraperitoneal dose: 4 mg/kg twice a week) significantly reduced the withdrawal response to cold stimulation. On the 12th day of drug administration, the L4-L6 DRG were removed and the expression of TRPM8 and TRPA1 mRNA was determined using RT-PCR. The expression of TRPM8 and TRPA1 in the DRG of rats that were coadministered GJG and Oxp decreased significantly compared with that in the rats administered Oxp alone. These results suggest that coadministration of GJG may improve Oxp-induced cold hypersensitivity by suppressing the overexpression of TRPM8 and TRPA1 mRNA.
Divisions of aClinical Pharmacokinetics bClinical Pharmacy, Department of Pharmaceutical Sciences, International University of Health and Welfare, Ohtawara, Japan.
Yoshinori
Y
Kato
Yoshikazu
Y
Tateai
Misao
M
Ohkubo
Yuka
Y
Saito
Syun-ya
SY
Amagai
Yu-Suke
YS
Kimura
Naohumi
N
Iimura
Megumi
M
Okada
Akiko
A
Matsumoto
Yasunari
Y
Mano
Iori
I
Hirosawa
Kaori
K
Ohuchi
Masataka
M
Tajima
Mariko
M
Asahi
Hajime
H
Kotaki
Harumi
H
Yamada
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D003080:Cold Temperature; D004365:Drugs, Chinese Herbal / Q000494:pharmacology* / Q000627:therapeutic use; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D012677:Sensation / Q000187:drug effects; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D009944:Organoplatinum Compounds; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050053:TRPM Cation Channels; C480976:Trpa1 protein, rat; C498947:Trpm8 protein, rat; C119642:gosha-jinki-gan; D000077150:Oxaliplatin