Rikkunshito prevents paclitaxel-induced peripheral neuropathy through the suppression of the nuclear factor kappa B (NFκB) phosphorylation in spinal cord of mice.
Peripheral neuropathy is the major side effect caused by paclitaxel, a microtubule-binding antineoplastic drug. Paclitaxel-induced peripheral neuropathy causes a long-term negative impact on the patient's quality of life. However, the mechanism underlying paclitaxel-induced peripheral neuropathy is still unknown, and there is no established treatment. Ghrelin is known to attenuate thermal hyperalgesia and mechanical allodynia in chronic constriction injury of the sciatic nerve, and inhibit the activation of nuclear factor kappa B (NFκB) in the spinal dorsal horn. Rikkunshito (RKT), a kampo medicine, increases the secretion of ghrelin in rodents and humans. Thus, RKT may attenuate paclitaxel-induced peripheral neuropathy by inhibiting phosphorylated NFκB (pNFκB) in the spinal cord. We found that paclitaxel dose-dependently induced mechanical hyperalgesia in mice. Paclitaxel increased the protein levels of spinal pNFκB, but not those of spinal NFκB. NFκB inhibitor attenuated paclitaxel-induced mechanical hyperalgesia suggesting that the activation of NFκB mediates paclitaxel-induced hyperalgesia. RKT dose-dependently attenuated paclitaxel-induced mechanical hyperalgesia. Ghrelin receptor antagonist reversed the RKT-induced attenuation of paclitaxel-induced mechanical hyperalgesia. RKT inhibited the paclitaxel-induced increase in the protein levels of spinal pNFκB. Taken together, the present study indicates that RKT exerts an antihyperalgesic effect in paclitaxel-induced neuropathic pain by suppressing the activation of spinal NFκB.
Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Junzo
J
Kamei
Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Shunsuke
S
Hayashi
Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Akane
A
Sakai
Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Yuki
Y
Nakanishi
Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Misa
M
Kai
Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Megumi
M
Ikegami
Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo, Japan.
Hiroko
H
Ikeda
D000818:Animals; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006930:Hyperalgesia / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D009437:Neuralgia / Q000378:metabolism / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017239:Paclitaxel / Q000009:adverse effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D018696:Neuroprotective Agents; C084136:liu-jun-zi-tang; D017239:Paclitaxel