Chronobiology of Melatonin beyond the Feedback to the Suprachiasmatic Nucleus—Consequences to Melatonin Dysfunction

Abstract

The mammalian circadian system is composed of numerous oscillators, which gradually differ with regard to their dependence on the pacemaker, the suprachiasmatic nucleus (SCN). Actions of melatonin on extra-SCN oscillators represent an emerging field. Melatonin receptors are widely expressed in numerous peripheral and central nervous tissues. Therefore, the circadian rhythm of circulating, pineal-derived melatonin can have profound consequences for the temporal organization of almost all organs, without necessarily involving the melatonin feedback to the suprachiasmatic nucleus. Experiments with melatonin-deficient mouse strains, pinealectomized animals and melatonin receptor knockouts, as well as phase-shifting experiments with explants, reveal a chronobiological role of melatonin in various tissues. In addition to directly steering melatonin-regulated gene expression, the pineal hormone is required for the rhythmic expression of circadian oscillator genes in peripheral organs and to enhance the coupling of parallel oscillators within the same tissue. It exerts additional effects by modulating the secretion of other hormones. The importance of melatonin for numerous organs is underlined by the association of various diseases with gene polymorphisms concerning melatonin receptors and the melatonin biosynthetic pathway. The possibilities and limits of melatonergic treatment are discussed with regard to reductions of melatonin during aging and in various diseases.

Melatonin maintains calcium-binding calretinin-positive neurons in the dentate gyrus during aging of Balb/C mice

“…Interestingly, the melatonin decline observed during aging, in Alzheimer's disease and in other dementias can be caused by deterioration of the suprachiasmatic nucleus (SCN), which acts as the circadian pacemaker (Farajnia et al, 2012;Nakamura et al, 2011;Skene et al, 1990;Skene and Swaab, 2003;Wu and Swaab, 2007). The involvement of the SCN in the decrease levels of melatonin has been recently reviewed (Hardeland, 2012(Hardeland, , 2013.…”

When the Circadian Clock Meets the Melanin Pigmentary System

“…During recent years, abundant evidence has accumulated regarding the importance of peripheral circadian oscillators (Fu and Kettner, 2013; Hardeland, 2013; Reiter et al , 2014). Some of these cellular clocks are to a variable extent autonomous and do not receive a direct input from the hypothalamic pacemaker, the suprachiasmatic nucleus (SCN) (Hardeland, 2013).…”

“…Some of these cellular clocks are to a variable extent autonomous and do not receive a direct input from the hypothalamic pacemaker, the suprachiasmatic nucleus (SCN) (Hardeland, 2013). However, they may be indirectly influenced by SCN-dependent cycles, such as the rhythms of glucocorticoids, ACTH, or melatonin.…”

“…However, they may be indirectly influenced by SCN-dependent cycles, such as the rhythms of glucocorticoids, ACTH, or melatonin. It must be noted that melatonin (Slominski et al , 2008; Hardeland, 2013; Reiter et al , 2014), ACTH, and glucocorticoids are also produced in peripheral organs including the skin (Slominski et al , 2013). The partial autonomy of peripheral cellular clocks must also be considered in the context of the cell cycle, which is gated by the respective circadian oscillator via controlling G1-, intra-S-, and G2/M checkpoints and modulating mitogenic signals (Fu and Kettner, 2013).…”

Melatonin, the Hormone of Darkness: From Sleep Promotion to Ebola Treatment

“…The neurohormone melatonin is not stored in the pineal gland but rather is released into the bloodstream and can penetrate all body tissues [11] . It is important to note that “darkness” stimulates the pineal gland to secrete melatonin whereas exposure to light inhibits this mechanism [12]. …”