Nitric Oxide production mediated by melatonin in a cell model of circadian rhythms

Pyranopyrazoles are known to exhibit a wide range of biological activities. 1-2 Some pyranopyrazoles have been evaluated for their bovine brain adenosine A 1 A 2A receptor binding affinity and these pyranopyrazoles are also of interest because of their structural similarity to a wide variety of flavones and flavanones that exhibit interesting biological activity. 1-2 Although the synthesis of some pyranopyrazoles has been known, the photochemical studies have not been reported. The pyrazole nucleus represents a very attractive scaffold for obtaining novel molecules endowed with diverse biological activity, Melatonin is an amphiphilic molecule secreted following a circadian cycle by the pineal gland, also produced in our body by other tissues and organs (retina, bone marrow, gut and skin). Nitric oxide (NO) is a gasotransmitter regulating, together with CO and H 2 S, several functions including mitochondrial respiration. The respiratory chain Complex IV (Cytochrome c Oxidase) is the main target of NO, whose binding at the active site of the enzyme induces its reversible inhibition. Pharmacological concentrations of melatonin (millimolar) have been known to exert antioxidant properties whereas the effects of physiological (nanomolar or less) endogenous-like concentrations, are still mostly obscure. We have recently reported that, in cultured cells, at such low concentrations melatonin induces a sudden, but reversible, increase of the intracellular expression of neuronal NOS, with a transient controlled release of nitrite/nitrate (NOx). On the same time scale, about 6 – 8 h, we have also observed depression of respiration and decreased ATP production, compensated by an increased production of lactate. These effects are exerted in a circadian compatible fashion and are reverted upon increasing the melatonin incubation time or its concentration. A mechanism involving the interaction of melatonin with cell receptors, nuclear activation and the intreacellular interaction with Ca ++-calmodulin is proposed to account for observations. c oxidase and nitric oxide in action: molecular mechanisms and pathophysiological implications. enhances nNOS expression and controls HaCaT-cells bioenergetics. New evidence for cross talk between melatonin and mitochondria mediated by a circadian-compatible interaction with nitric oxide. Reactive oxygen species (ROS) generated within the vascular wall trigger LDL oxidation, lipid peroxidation and carbonyl stress that are involved in atherogenesis. The generation of drugs sharing both antioxidant cytoprotective and/or carbonyl scavenger properties may represent a new therapeutic challenge in the prevention and treatment of atherosclerosis. Families of compounds based on the phenolic phosphonates derived from cinnamic acids with antioxidant activities have been developed in …