Involvement of hypothalamic cyclooxygenase-2, interleukin-1β and melanocortin in the development of docetaxel-induced anorexia in rats.
Docetaxel, a taxane derivative, is frequently used for the treatment of advanced breast cancer, non-small cell lung cancer, and metastatic prostate cancer. Clinical reports demonstrated that docetaxel-based chemotherapy often induces anorexia, but the etiology is not completely understood. To elucidate possible mechanisms, we investigated the involvement of central interleukin (IL)-1β, cyclooxygenase (COX)-2, and pro-opiomelanocortin (POMC) in the development of docetaxel-induced anorexia in rats. Rats received docetaxel (10mg/kg, i.p.) with or without pretreatment with selective COX-2 inhibitors, NS-398 (10 and 30 mg/kg, i.g.) or celecoxib (10 and 30 mg/kg, i.g.), and a non-selective COX inhibitor, indomethacin (10mg/kg, i.g.), then food intake was monitored for 24h after administration. We also examined expression of IL-1β, COX-2, and POMC mRNA in hypothalamus of docetaxel-treated rats and the effect of a COX-2 inhibitor on docetaxel-induced POMC mRNA expression. Food consumption in rats was significantly decreased 24h after administration of docetaxel and anorexia was partially reversed by all COX inhibitors. Administration of docetaxel increased IL-1β, COX-2, and POMC mRNA expression in the hypothalamus of rats. The time required to increase these gene expressions was comparable to the latency period of docetaxel-induced anorexia in rats. In addition, pretreatment with COX-2 inhibitors suppressed docetaxel-induced expression of POMC mRNA. These results suggest that IL-1β and COX-2 mRNA expression and subsequent activation of POMC in the hypothalamus may contribute to the development of docetaxel-induced anorexia in rats.
Laboratory of Pharmacology, Department of Medical Science and Technology, Division of Health Sciences, Graduate School of Medicine, Osaka University, Yamadaoka 1-7, Suita, Osaka, Japan. kouichi@sahs.med.osaka-u.ac.jp
Kouichi
K
Yamamoto
Keiko
K
Asano
Yui
Y
Ito
Naoki
N
Matsukawa
Seikou
S
Kim
Atsushi
A
Yamatodani
D000818:Animals; D000855:Anorexia / Q000139:chemically induced* / Q000473:pathology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D000077143:Docetaxel; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009578:Nitrobenzenes / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D043823:Taxoids / Q000009:adverse effects*
D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D009578:Nitrobenzenes; D011720:Pyrazoles; D013449:Sulfonamides; D043823:Taxoids; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000077143:Docetaxel; D011333:Pro-Opiomelanocortin; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000068579:Celecoxib; D007213:Indomethacin