The events associated with brain aging are enumerated with emphasis on increased oxidative and inflammatory processes and on mitochondrial dysfunction. Several of these factors are further increased in a wide range of overt age-related neurological diseases. This generality has given impetus to concepts concerning similar therapeutic approaches common to a series of neurodegenerative disorders. Animal and cell culture models of several such disorders have benefited from the application of melatonin. The mechanisms underlying the neuroprotective properties of melatonin are likely to involve activation of specific melatonin receptors. This can lead to modulation of transcription factors and consequent altered gene expression, resulting in enhancement of antioxidant enzymes and downregulation of basal levels of inflammation. Melatonin has potential utility both in slowing normal brain aging and in treatment of neurodegenerative conditions. This is reinforced by the low cost of melatonin and its very low toxic hazard. © 2007.

Melatonin is an indoleamine with the chemical name N-acetyl-5-methoxytryptamine and is found in animals, plants, and bacteria. It has endocrine properties in both animals and plants. It is biosynthesized from the neurotransmitter, serotonin, which in turn is made from the essential amino acid, tryptophan. Because its 5-hydroxy and charged amino groups are both acetylated, it is a relatively nonpolar compound. In mammals, melatonin has several roles; it is involved in circadian regulation and modulation of reproductive and immune responses, mood, and aging. It is produced by the pineal gland and several peripheral tissues, notably the gut. Because it is liberated into the bloodstream from the pineal, it can be considered a systemic hormone. Levels of melatonin vary diurnally, being highest during hours of darkness, and also vary throughout the life cycle, being lowest among the elderly. This chapter focuses on recent findings suggesting a variety of therapeutic applications and supporting the safety of exogenously supplied melatonin. The potential molecular mechanisms underlying these potentially clinically beneficial uses are also discussed.

With an estimated incidence exceeding 1.1 million cases per year in the United States (Moore and Moore, 2012), sepsis is the 10th leading cause of death overall in this country (Yang et al., 2010). As of 2005, “mortality of severe sepsis exceeds other high-prole diseases such as AIDS, venous thromboembolism, and both lung and colon cancers” (Jones, 2006). Moreover, septic shock-related mortality is greater than 40%, and sepsis itself is the leading cause of death in noncardiac intensive care units (Moore and Moore, 2012). Little progress in reducing sepsis is being made: to the contrary, between 2003 and 2007, hospitalizations for severe sepsis in the United States increased by 71% and in 2007 incurred a cost of $24.3 billion (Lagu et al., 2012). Mortality rates have decreased little in the past 30 years (Astiz and Rackow, 1998). As of 2005, multidrug-resistant bacteria and fungi were noted to cause about 25% of cases (Annane et al., 2005), increasing the importance for identifying adjuvant treatments capable of strengthening the immune system of patients.

The ability of melatonin treatment of aged animals to partially restore the pattern of gene expression characterizing the younger animal has been frequently reported. The current study examines the effect of melatonin upon age-related changes of some key proteins relevant to the aging process. Male B6C3F1 mice, aged 5.5 months and 23.4 months were used as a model for aging and half of each group received a diet supplemented with 40-ppm (w/w) melatonin for 9.3 weeks. Protein components of the globus pallidus were studied including glial fibrillary acidic protein (GFAP), NF-κB, protein disulfide isomerase (PDI), and Nissl staining. Some age-related changes were in an upward direction (GFAP and NF-κB), while others were depressed with age (PDI and intensity of Nissl staining). However, in either case, melatonin treatment of aged mice generally altered these parameters so that they came to more closely resemble the levels found in younger animals. The extent of this reversal to a more youthful profile, ranged from complete (for NF-κB) to very minor (for Nissl staining and PDI). Overall, these findings are in accord with prior data on the effect of melatonin on cortical gene expression and confirm the value of melatonin as a means of retarding events associated with senescence.