Decline In Melatonin Levels Research Articles

New melatonin derivatives with donepezil fragment in Alzheimer’s disease as neuroprotectors

AbstractBackgroundAlzheimer’s disease is characterized by progressive, irreversible degeneration of acetylcholine‐producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The natural decline in melatonin levels with aging has been associated with insomnia and depression as well as the development of neurodegenerative disorders such as AD. Furthermore, the complexity of AD pathology has encouraged the design of molecules that are able to interact with two or more complementary targets, with the expectation that these multitarget ligands (MTL) may represent important advantages in the treatment of the disease. This study aimed to find new ChE inhibitors with improved toxicity.Method In vitro toxicity screening of the newly compounds on human neuroblastoma SH‐SY5Y, mouse neuroblastoma cell line Neuro‐2a and mouse fibroblast cells CCL‐1. The viability of the cells was assessed by MTT assay. The neuroprotective properties of the compounds were determined in a model of H2O2‐induced oxidative damage in SH‐SY5Y cells. For comparison, effects donepezil, melatonin and galanthamine were determined.ResultMost of the compounds have IC50 values over 100 µM. Compound 3f possess statistically significant protective effects. It should be noted that the neuroprotective effects were more pronounced than those of donepezil and similar to melatonin and rasagiline.ConclusionThe new series of melatonin derivatives with donepezil fragment exhibit low toxicity and a good in vitro safety profile. Further, in vitro protection study proved efficient prevention against oxidative stress in H2O2‐induced injury in SH‐SY5Ycells, especially by compound 3f and was proven as the most perspective for further investigations.Acknowledgments: The financial support by the National Science Fund of Bulgaria (Grant KP‐06‐Н63/11 14.12.2022) is gratefully acknowledged.

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

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.

A Review of the Potential Effects of Melatonin in Compromised Mitochondrial Redox Activities in Elderly Patients With COVID-19.

Melatonin, an endogenous indoleamine, is an antioxidant and anti-inflammatory molecule widely distributed in the body. It efficiently regulates pro-inflammatory and anti-inflammatory cytokines under various pathophysiological conditions. The melatonin rhythm, which is strongly associated with oxidative lesions and mitochondrial dysfunction, is also observed during the biological process of aging. Melatonin levels decline considerably with age and are related to numerous age-related illnesses. The signs of aging, including immune aging, increased basal inflammation, mitochondrial dysfunction, significant telomeric abrasion, and disrupted autophagy, contribute to the increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These characteristics can worsen the pathophysiological response of the elderly to SARS-CoV-2 and pose an additional risk of accelerating biological aging even after recovery. This review explains that the death rate of coronavirus disease (COVID-19) increases with chronic diseases and age, and the decline in melatonin levels, which is closely related to the mitochondrial dysfunction in the patient, affects the virus-related death rate. Further, melatonin can enhance mitochondrial function and limit virus-related diseases. Hence, melatonin supplementation in older people may be beneficial for the treatment of COVID-19.

Awakening effects of blue-enriched morning light exposure on university students\u2019 physiological and subjective responses

We investigated physiological and subjective responses to morning light exposure of commercially available LED lighting with different correlated colour temperatures to predict how LED-based smart lighting employed in future learning environments will impact students. The classical markers of the circadian system (melatonin and cortisol), as well as the subjective perception of sleepiness, mood, and visual comfort, were compared. Fifteen university students underwent an hour of morning light exposure to both warm (3,500 K) and blue-enriched (6,500 K) white lights at recommended illuminance levels for classrooms and lecture halls (500 lux). The decline of melatonin levels was significantly greater after the exposure to blue-enriched white light. Exposure to blue-enriched white light significantly improved subjective perception of alertness, mood, and visual comfort. With regard to cortisol, we did not find a significant difference in the cortisol decrement between the two light conditions. Our findings suggest that the sensitivity of physiological and subjective responses to white LED light is blue-shifted. These findings, extending the already known effects of short-wavelength light on human physiology, reveal interesting practical implications. Blue-enriched LED light seems to be a simple yet effective potential countermeasure for morning drowsiness and dozing off in class, particularly in schools with insufficient daylight.

Modulation of serine/threonine phosphatases by melatonin: therapeutic approaches in neurodegenerative diseases.

Melatonin is an endogenous hormone produced by the pineal gland as well as many other tissues and organs. The natural decline in melatonin levels with ageing contributes significantly to the development of neurodegenerative disorders. Neurodegenerative diseases share common mechanisms of toxicity such as proteinopathy, mitochondrial dysfunction, metal dyshomeostasis, oxidative stress, neuroinflammation and an imbalance in the phosphorylation/dephosphorylation ratio. Several reports have proved the usefulness of melatonin in counteracting the events that lead to a neurodegenerative scenario. In this review, we have focused on the fact that melatonin could rectify the altered phosphorylation/dephosphorylation rate found in some neurodegenerative diseases by influencing the activity of phosphoprotein phosphatases. We analyse whether melatonin offers any protective activity towards these enzymes through a direct interaction. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.

The influence of light on thermal responses.

Light is essential for vision and plays an important role in non-visual responses, thus affecting alertness, mood and circadian rhythms. Furthermore, light influences physiological processes, such as thermoregulation, and therefore may be expected to play a role in thermal comfort (TC) as well. A systematic literature search was performed for human studies exploring the relation between ocular light exposure, thermophysiology and TC. Experimental results show that light in the evening can reduce melatonin secretion, delay the natural decline in core body temperature (CBT) and slow down the increase in distal skin temperature. In the morning though, bright light can result in a faster decline in melatonin levels, thus enabling a faster increase in CBT. Moreover, the colour of light can affect temperature perception of the environment. Light with colour tones towards the red end of the visual spectrum leads to a warmer perception compared to more bluish light tones. It should be noted, however, that many results of light on thermal responses are inconclusive, and a theoretical framework is largely lacking. In conclusion, light is capable of evoking thermophysiological responses and visual input can alter perception of the thermal environment. Therefore, lighting conditions should be taken into consideration during thermophysiological research and in the design of indoor climates.

Melatonin, Gestation and Fetal Development

The gland, the transducer of several environmental cues through its hormone, melatonin, is known to play a critical role in the reproduction of several seasonally breeding mammals. The role of gland in the control of male reproduction is already established beyond doubt. The logical hypothesis that the gland would be involved in the aspects of female reproduction, particularly gestation, embryonic development and fetal growth, has been tested in a few seasonally breeding mammals and this paper reviews the outcome as of now. Evidence for establishment of an inverse relationship before pregnancy followed by moderately high activity with a positive correlation during pregnancy and a sudden increase in activity during parturition has been produced, which suggests that high melatonin level has something to do with parturition or early abortion. The gland perhaps maintains the normal physiology during gestation and post-parturition periods. This is further reflected in the prolactin levels of fetal sheep which is modulated by the photoperiod experienced by the mother during gestation. Maternal photoperiodic exposures during gestation and lactation periods alter the neonatal growth and sexual maturation of the Indian palm squirrel via the maternal transfer of photoperiodic information through the gland, as aspect known as pineal programming. The primary source of melatonin for the fetus is the maternal gland, which is transferred across the placenta during conception and, later after parturition, through the milk, which suggests that a maternally generated melatonin rhythm would be expressed in fetal cerebrospinal fluid as well as in the circulation. Further, maternal melatonin is necessary for normal somatic growth and postnatal development of reproductive organs of the offspring. Melatonin ultimately affects reproductive activity by modulating hypothalamic neuroendocrine circuits whose activity is necessary for gonadal function. The influence of melatonin on reproductive development begins during the prenatal period and extends into the postnatal life. Photoperiodic information, mediated via the gland may be important for maintaining gestational physiology as well as postpartum recovery in female rodents. Further, melatonin has been shown to play adaptive role in the maintenance of delayed embryonic development in bats. Correlation between a developmental decline in melatonin levels and the timing of puberty in humans led to the speculation that melatonin regulates the timing of puberty in the human. These studies on the influence of melatonin on gestation indicate two major inferences viz., melatonin could be one of the major hormones establishing homeostasis during gestation since any disturbance in the level of melatonin causes abortion, and melatonin is one of the hormones of great adaptive significance for embryonic diapause.

The effect of variations in pH and temperature on stability of melatonin in aqueous solution.

Melatonin (N-acetyl-5-methoxytryptamine) has a diverse range of functions, including the control of neuroendocrine events. A number of studies have shown that melatonin may be of potential benefit for the treatment of insomnia, as well as neurodegenerative disorders. At present, there are numerous dosage forms of melatonin, with the oral route of administration being most popular. Presently, there is little information on the stability of melatonin over a pH range. With the changes in pH in the gastro-intestinal tract, as well as in different experimental conditions, information on the stability of melatonin would be important. We used a high-performance liquid chromatography method to determine the stability of melatonin solutions over a pH range (1.2-12) at room temperature and at 37 degrees C over a period of 21 days. The results show that no melatonin degradation occurred in the first 2 days. From days 3 to 21, there was a gradual decline in melatonin at all pHs, with the decline not exceeding 30%. No decline in melatonin levels occurred in the first 2 days at 37 degrees C. From days 3 to 21, melatonin levels declined gradually, with the decline not exceeding 29%.

Self-report of circadian type reflects the phase of the melatonin rhythm

This study examined the relationship between circadian rhythm characteristics of the pineal hormone melatonin and individual differences in circadian type and mood. 95 healthy young men and 22 women were assessed each hour (00:00–07:00 h) for blood levels of melatonin throughout one night in the laboratory. Each subject was assessed for circadian type (morning, afternoon, or evening type) and morning mood (PANAS). Circadian type was strongly related to the melatonin acrophase but not to amplitude or time of year of assessment. Also, morning types evidenced a more rapid decline in melatonin levels after the peak than did evening types. Evening types were younger than were morning types. Female morning types reported more positive affect upon waking than did female afternoon or evening types. Males showed no such discrimination. Age was related to both melatonin acrophase and circadian type but did not explain the relationship between them. The results replicate and extend findings on circadian type and psychological and physiological variables.

Treatment With AC Pulsed Electromagnetic Fields Prevents Seasonal Exacerbation of Symptoms in Multiple Sclerosis

Seasonal variation in symptoms of multiple sclerosis (MS) has been well documented in the literature and points to the influence of environmental factors on the pathogenesis of the disease. The majority of these studies indicate an increased rate of exacerbation during the spring and/or autumn both of which are associated with desynchronization of circadian pineal melatonin secretion with nadirs in plasma melatonin levels. Three MS patients who experienced annually recurrent and incapacitating seasonal exacerbations of existing symptoms are presented. The first patient, a 49 year old woman, developed over the past 6 years recurrent exacerbations of symptoms in the spring which lasted for about a month. The second patient, a 53 year old woman, experienced over the past 7 years recurrent exacerbations of symptoms in the autumn which lasted through January of the following year. The third patient, a 42 year old woman, experienced recurrent exacerbations of symptoms in the spring and autumn over the past 15 years. In these patients, intermittent transcranial treatments with AC pulsed electromagnetic fields (EMFs) of 7.5 picotesla flux density produced a significant decrease in motor disability and additionally prevented seasonal exacerbations of symptoms. Since the pineal gland functions as a neuroendocrine transducer and an immunoregulator, it is believed that desynchronization of circadian melatonin secretion associated with a decline in melatonin levels during the spring and autumn facilitated exacerbation of the disease. The pineal gland is a magneto-sensor organ and pulsed applications of these EMFs may have synchronized circadian melatonin rhythms and thus prevented seasonal exacerbations of symptoms.

Cyclic AMP and Butyrate Modulate Melatonin Synthesis in Y79 Human Retinoblastoma Cells

Melatonin is synthesized by cultured Y79 human retinoblastoma cells and is secreted into the medium. Activity of the two key enzymes involved in the synthesis of melatonin, N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), are present in retinoblastoma cells. The activity of these enzymes and the resulting synthesis and release of melatonin are modulated by the addition of a cyclic AMP analogue and butyrate to the culture medium. Melatonin levels increase dramatically over control levels after the addition of dibutyryl cyclic AMP (dbcAMP), whereas melatonin levels decrease after butyrate treatment. HIOMT activity is inhibited by both dbcAMP and butyrate, and NAT activity is stimulated by both of these differentiating agents, suggesting that the rise in melatonin levels in response to dbcAMP is the result of increased activity of NAT, whereas the decline in melatonin levels in response to butyrate may be due to a drop in HIOMT activity. Melatonin synthesis is dose- and time-dependent, and the effect of dbcAMP is readily reversible, whereas the effect of butyrate does not appear to be reversible. These effects probably reflect basic differences in the regulatory mechanisms of the inducing agents.