A novel dual regulator of tumor necrosis factor-α and interleukin-10 protects mice from endotoxin-induced shock

• Published in: European journal of pharmacology Vol. 391; no. 3; pp. 317 - 320
• Main Authors: Fukuda, Tetsuko, Sumichika, Hiroshi, Murata, Meguru, Hanano, Tokushi, Adachi, Kunitomo, Hisadome, Masao
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 17.03.2000; Elsevier
• Subjects: Acetamides - administration & dosage; Acetamides - pharmacology; Administration, Oral; Animals; Biological and medical sciences; Cardiovascular system; Endotoxins; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Female; Interleukin-10; Interleukin-10 - biosynthesis; Lipopolysaccharide; Lipopolysaccharides; Medical sciences; Mice; Mice, Inbred BALB C; Miscellaneous; Pharmacology. Drug treatments; Piperazines - administration & dosage; Piperazines - pharmacology; Shock, Septic - chemically induced; Shock, Septic - metabolism; Shock, Septic - mortality; Shock, Septic - prevention & control; TNF-α; Tumor Necrosis Factor-alpha - biosynthesis; tumor necrosis factor-α; Interleukin-10; TNF-α; Lipopolysaccharide; Shock; Treatment efficiency; Interleukin; Cytokine; Rodentia; Cardioprotective agent; Oral administration; Cardiovascular disease; Biological activity; Infection; Prevention; Vertebrata; Chemotherapy; Regulation(control); Mammalia; Treatment; Mouse; Animal; Interleukin 10; Mechanism of action; Tumor necrosis factor α
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(00)00096-0

A pyrimidylpiperazine derivative, N-[1-(4-{[4-(pyrimidin-2-yl)piperazin-1-yl]methyl}phenyl)cyclopropyl]acetamide (Y-39041), is a dual cytokine regulator of tumor necrosis factor (TNF)-α and interleukin-10 production. Lipopolysaccharide-induced TNF-α release in BALB/c mice was inhibited by the oral treatment with the compound at 10–100 mg/kg (about 80% suppression) while interleukin-10 release was augmented (about 10-fold increase at 30 mg/kg). In addition, Y-39041 (30 mg/kg, p.o.) completely protected mice from lipopolysaccharide-induced death by the treatment before and after lipopolysaccharide injection. The finding that Y-39041 suppresses TNF-α production and stimulates interleukin-10 production at the same time provides new insights for the treatment of septic shock, rheumatoid arthritis and Crohn's diseases.