Evaluation of the therapeutic potential of modulating the of immune-pineal axis in an animal model of lethal systemic inflammation

Abstract

In the mounting phase of inflammatory responses, the activation of the immune pineal axis facilitates leukocyte migration to peripheral tissues by inhibiting the production of melatonin by the pineal gland, and locally modulates the immune response due to the production of melatonin by peripheral immunocompetent cells and by glial cells of the central nervous system. Restoring the production of melatonin by the pineal gland and the suppression of its production by extra-pineal sources are essential for the proper regulation of inflammation intensity. Unregulated processes that do not regulate the inflammatory response may result in death of the individual. Thus, it is important to understand the differences in the pattern of the immune-pineal axis activation between lethal and nonlethal situations. In this projected, we will compare the activation of the immune-pineal axis (inhibition/stimulation of the production of melatonin by the pineal and by extra-pineal sources, in the periphery and in the nervous system) in rats injected with lethal and nonlethal dose of LPS. Melatonin dosages will be associated with the determination of the melatonin receptors expression (MT1 and MT2) in the cells and tissues. In addition, it will be evaluate the efficacy of pharmacological (melatonergic agonists and antagonists) or physical (electroacupuncture) interventions in reducing the lethality of systemic inflammation. The expectation is that the adjustment of the melatonergic system activation can reverse the mortality induced by high doses of LPS, and that we can base the proposition of therapeutic strategies for lethal inflammation by understanding the endogenous relevance of the immune-pineal axis. (AU)