MECHANISM OF THE INHIBITORY EFFECT OF MELATONIN ON TUMOR-NECROSIS-FACTOR PRODUCTION IN-VIVO AND IN-VITRO

Melatonin is an antioxidant. Since other antioxidants inhibit the prod uction of tumor necrosis factor (TNF) induced by lipopolysaccharide, w e investigated its effect on TNF production in vivo and in vitro and o n lethality associated with endotoxic shock. Administration of melaton in to mice (5 mg/kg, s.c., 30 min before or simultaneously with lipopo lysaccharide) inhibited serum TNF levels by 50-80% and improved surviv al of mice treated with a lethal dose of lipopolysaccharide. By studyi ng other, structurally related, indolamines (N-acetyl-5-hydroxytryptam ine, 5-methoxytryptamine and 5-hydroxytryptamine) we found a good corr elation between antioxidant activity (for which the 5-methoxy group is essential) and the inhibition of TNF production in vivo and in vitro in mononuclear cells. Melatonin did not increase serum corticosterone and did not modify the elevation of serum corticosterone levels by lip opolysaccharide or by interleukin-l. Furthermore, it exerted its inhib itory effect in adrenalectomized or hypophysectomized mice also, indic ating that its effect is independent of the hypothalamus-pituitary-adr enal axis. (C) 1998 Elsevier Science B.V.