Neurochemical Research, Vol. 28, No. 5, May 2003 (© 2003), pp. 681–686 681 0364-3190/03/0500–0681/0 © 2003 Plenum Publishing Corporation Melatonin Increases Interleukin-1b and Decreases Tumor Necrosis Factor Alpha in the Brain of Mice Infected with the Venezuelan Equine Encephalomyelitis Virus Ernesto Bonilla, 1,2,3 Nereida Valero, 1 Leonor Chacín-Bonilla, 1 Héctor Pons, 1 Yraima Larreal, 1 Shirley Medina-Leendertz, 2 and Luz Marina Espina 1 (Accepted August 9, 2002) The effect of melatonin (MLT) on the brain levels of tumor necrosis factor alpha (TNF-a) and interleukin-1b (IL-1b) in Venezuelan equine encephalomyelitis (VEE) virus infection was de- termined. Brain homogenates from mice inoculated with 10 LD 50 of VEE virus, untreated or treated with 500 mg MLT/kg body weight were assayed by ELISA to measure the levels of TNF-a and IL-1b. MLT was injected daily starting 3 days before and continuing to 7 days after virus inoculation. Infected mice treated with MLT showed decreased levels of TNF-a when com- pared to the untreated infected mice on days 1, 3, 4, and 5 postinoculation (P , 0.001). In con- trast, IL-1b levels increased from days 1 to 5 in the infected mice treated with MLT when compared with the untreated infected animals (P , 0.01). The results suggest that the protective effect of MLT on the VEE virus infection could be due, among other factors, to a decrease in TNF-a synthesis along with an increase in the production of IL-1b. KEY WORDS: Melatonin; Venezuelan equine encephalomyelitis virus; tumor necrosis factor-alpha; interleukin-1b. 1 Instituto de Investigaciones Clínicas “Dr. Américo Negrette,” Fac- ultad de Medicina, Universidad del Zulia, Apartado postal 1151, Maracaibo, Venezuela. 2 Departamento de Neurobiología, Instituto de Investigaciones Bio- médicas (INBIOMED), FUNDACITE-ZULIA, Apartado postal 121, Maracaibo, Venezuela. 3 Address reprint requests to: Ernesto Bonilla, Instituto de Investi- gaciones Clínicas “Dr. Américo Negrette,” Facultad de Medicina, Universidad del Zulia, Apartado postal 1151, Maracaibo, Venezuela. Tel: 158-261-7597247; Fax: 158-261-7835587; E-mail: ebonillaro@ yahoo.com INTRODUCTION Melatonin (MLT, N-acetyl-5-methoxytryptamine) appears to be involved in synchronizing the circadian and seasonal timing of several physiological and be- havioral processes (1,2), and it seems to be a powerful hydroxyl-radical scavenger that provides on-site pro- tection against oxidative damage to cell components (3). Because of its high solubility on lipids and high degree of hydrophilicity (4), this hormone not only crosses the cell membrane to enter the cytosol, but it also has ac- cess to every subcellular compartment without the help of a carrier molecule (3). MLT plays an important im- munoregulatory role in both physiological and phys- iopathological conditions (5,6). By binding to T-helper cells, MLT gives rise to a series of events leading to an increase in immune response (7) that seems to be medi- ated, at least in part, by endogenous opioid peptides (8), and T-cell–derived cytokines (9). In fact, when chroni- cally injected into young mice or those immunode- pressed by aging or cyclophosphamide, MLT was able to enhance the antibody response to a T-dependent antigen (10). A protective effect of MLT was reported in mice infected with the Semliki Forest virus (SFV) and in stressed mice infected with the attenuated noninvasive