THE PINEAL NEUROHORMONE MELATONIN PREVENTS IN-VIVO AND IN-VITRO APOPTOSIS IN THYMOCYTES

Recently, melatonin was found to be the most potent physiological free radical scavenger known to date. In this work, we attempted to define the role this neurohormone plays in the regulation of apoptosis, sinc e the effect of bcl-2, the main gene implicated in its inhibition, act s via an antioxidant mechanism. We investigated the role of melatonin in cell death of thymus, a well known model for the study of apoptosis . Two sets of experiments were carried out: in vivo experiments, perfo rmed with Wistar rats, and in vitro experiments, performed with primar y cultures of young Wistar rat thymocytes treated with glucocorticoids in order to induce apoptosis. Morphometrical studies in semithin sect ions of thymus and analysis of DNA fragmentation by,eel electrophoresi s show that physiological apoptosis occurring in thymus of 65 days old rats, is prevented by the daily administration of melatonin beginning when the rats were 25 days old. Also, we found that at a concentratio n of 10(-7) M, melatonin decreases by 35% the percentage of apoptotic cells induced by glucocorticoids in cultured thymocytes of 25 day old rats. 10(-9) M melatonin decreases cell death by 20%. Finally, melaton in at 10(-11) M did not have any effect. Several hypothesis are discus sed to explain this effect: direct interaction of melatonin with gluco corticoid receptors in the thymus; induction of interleukin-4 release; direct genomic action modulating the expression of apoptosis-inhibiti ng genes; an effect on nitric oxide synthase; and finally, the antioxi dant action of melatonin. Since apoptosis is a possible mechanism invo lved in neuronal death shown in several neurodegenerative diseases suc h as Parkinson or Alzheimer's diseases, investigative efforts should b e directed to the possible role of melatonin in inhibiting cell death in tissues other that the thymus. Melatonin might be a potent therapeu tic agent in some of these conditions.