Anti-inflammatory drugs ameliorate opposite enzymatic changes in ileal 5-hydroxytryptamine metabolism in the delayed phase after cisplatin administration to rats.
The effects of anti-inflammatory drugs on ileal 5-hydroxytryptamine (5-HT) metabolic dynamics at 72 h after a single administration of cisplatin were investigated in rats. Cisplatin 5 mg/kg i.p. caused pathological changes, with an inflammatory response occurring 72 h after its administration. The inflammatory response was associated with the induction of cyclooxygenase-2, but not cyclooxygenase-1, in the ileal mucosa at 72 h after the cisplatin administration. Daily treatment with meloxicam 3 mg/kg s.c. ameliorated the cisplatin-induced mucosal damage, whereas dexamethasone 1 mg/kg s.c. did not. Cisplatin administration also caused a significant increase in cyclooxygenase-2 mRNA expression at 72 h after administration, which was blunted by dexamethasone, but not by meloxicam. Cisplatin increased the content of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), but had no effect on 5-HT turnover (5-HIAA/5-HT ratio). Meloxicam and dexamethasone did not significantly decrease 5-HT and 5-HIAA content. Cisplatin significantly decreased monoamine oxidase activity but increased tryptophan hydroxylase (TPH) activity and TPH(1) mRNA expression in ileal tissue. Meloxicam and dexamethasone significantly restored the decreased monoamine oxidase activity and inhibited the cisplatin-induced increase in tryptophan hydroxylase activity toward the control levels. These drugs also decreased the cisplatin-induced increase in TPH(1) mRNA expression. Neither cisplatin nor the anti-inflammatory drugs had significant effect on mRNA expression of the serotonin re-uptake transporter. These results suggest that the inflammatory response associated with cyclooxygenase-2 induction is involved in the opposite change in ileal tryptophan hydroxylase and monoamine oxidase activities in the delayed phase after single administration of cisplatin to rats.
Department of Pharmacological Sciences, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan.
Chuanxia
C
Ju
Naoya
N
Hamaue
Takuji
T
Machida
Yanxia
Y
Liu
Kenji
K
Iizuka
Yue
Y
Wang
Masaru
M
Minami
Masahiko
M
Hirafuji
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004790:Enzyme Induction; D004794:Enzyme Repression; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007079:Ileitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D007082:Ileum / Q000187:drug effects* / Q000201:enzymology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D008297:Male; D000077239:Meloxicam; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008995:Monoamine Oxidase / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D014365:Tryptophan Hydroxylase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D013843:Thiazines; D013844:Thiazoles; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D003907:Dexamethasone; D014365:Tryptophan Hydroxylase; C504570:tph1 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D008995:Monoamine Oxidase; D002945:Cisplatin; D000077239:Meloxicam