A role for the regulation of the melatonergic pathways in Alzheimer's disease and other neurodegenerative and psychiatric conditions

When tryptophan is taken up by the body, some is used for the synthesis of serotonin. As well as having neuroregulatory effects, serotonin is also the precursor for the synthesis of N-acetylserotonin (NAS) and melatonin, which form the melatonergic pathways. The melatonergic pathways are associated with many of the changes that are thought to be important in the pathophysiology of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and major depressive disorder. As well as being produced by the pineal gland at night, and thereby contributing to the circadian rhythm, melatonin is also very highly produced in other organs and tissues, including the gut, where it may have an important role in the regulation of gut permeability and thereby with many medical conditions. Melatonin significantly regulates the immune system, affording protection against immune senescence and the patterning of the immune responses. Recent work on central nervous system (CNS)-associated disorders suggest that altered immune responses are an integral part of their etiology, course, and treatment. Melatonin is also a significant antioxidant and anti-inflammatory as well as optimizing mitochondrial functioning. Melatonin may be produced by many, if not all, human cells, including central glia and immune cells, where autocrine and paracrine effects of melatonin generally decrease the reactivity of these cells. This is important, as glia and immune reactivity are significant pharmaceutical targets. NAS, the immediate precursor of melatonin, is also a powerful antioxidant. Some NAS effects may be mediated by its ability to mimic brain-derived neurotrophic factor (BDNF), which is commonly decreased in many CNS conditions. Many factors that are associated with benefit in CNS conditions may actually be mediating their benefit by increasing the synthesis of melatonin in a wide array of cells. This chapter reviews the melatonergic pathway's role in such CNS medical conditions, highlighting its use for a whole host of conditions that are currently very poorly managed.