Melatonin as a Harmonizing Factor of Circadian Rhythms, Neuronal Cell Cycle and Neurogenesis: Additional Arguments for Its Therapeutic Use in Alzheimer’s Disease

Abstract

The synthesis and release of melatonin in the brain harmonize various physiological functions. The apparent decline in melatonin levels with advanced aging is an aperture to the neurodegenerative processes. It has been indicated that down regulation of melatonin leads to alterations of circadian rhythm components, which further causes a desynchronization of several genes and results in an increased susceptibility to develop neurodegenerative diseases. Additionally, as circadian rhythms and memory are intertwined, such rhythmic disturbances influence memory formation and recall. Besides, cell cycle events exhibit a remarkable oscillatory system, which is downstream of the circadian phenomena. The linkage between the molecular machinery of the cell cycle and complex fundamental regulatory proteins emphasizes the conjectural regulatory role of cell cycle components in neurodegenerative disorders such as Alzheimer’s disease. Among the mechanisms intervening long before the signs of the disease appear, the disturbances of the circadian cycle, as well as the alteration of the machinery of the cell cycle and impaired neurogenesis, must hold our interest. Therefore, in the present review, we propose to discuss the underlying mechanisms of action of melatonin in regulating the circadian rhythm, cell cycle components and adult neurogenesis in the context of AD pathogenesis with the view that it might further assist to identify new therapeutic targets.

Bases celulares y moleculares de la cronopatología en la enfermedad de Alzheimer

“…En términos prácticos, esto puede ser importante ya que se ha encontrado que los pacientes con EA estaban menos expuestos a la luz ambiental que sus controles de la misma edad, de modo que la disfunción del NSQ se agravó por la baja intensidad de la luz (señal de sincronización). 64 De hecho, se ha comprobado que esta exposición a la luz brillante en fases circadianas seleccionadas alivia notablemente los síntomas del síndrome de la puesta del sol y mejora los patrones de ondas del sueño en pacientes con EA. El síndrome de la puesta del sol o síndrome crepuscular es un fenómeno cronobiológico típico observado en la EA, junto con alteraciones del ciclo sueño/vigilia.…”

Potential Neuroprotective Role of Melatonin in Sepsis-Associated Encephalopathy Due to Its Scavenging and Anti-Oxidative Properties

“…The most important source of melatonin in humans is the pineal gland, where this neurohormone is produced with the circadian rhythm, but multiple local sources of melatonin also exist, like the retina [ 29 ], immune cells [ 30 ], skin [ 31 ] or the epithelium of the gastrointestinal tract [ 32 ]. The most noticeable physiological role of melatonin in humans is the control of the circadian rhythm [ 33 , 34 ], but it exerts numerous other effects. Melatonin is a potent antioxidant [ 35 ] and anti-inflammatory factor [ 36 ].…”

Borolatonin limits cognitive deficit and neuron loss while increasing proBDNF in ovariectomised rats

“…In fact, melatonin, and its receptors (MT1 and MT2) have attracted attention in that there is an inverse correlation between the levels of melatonin in cerebrospinal fluid and the severity of the neuropathology [6]. Also, there are authors who report melatonin, not just as a physiological regulator of circadian rhythms, if not a harmonizing factor of neuronal cell cycle and neurogenesis [7]. Moreover, along with cognitive impairment related to aging, a disturbed circadian rhythm is a key factor in AD evolution, as a link between circadian rhythms, sleep, and AD has been well-documented [8].…”