Posts tagged melatonin
Articles and news from the latest research reports.
A hormone that governs sleep and jet lag in humans may also drive the mass migration of plankton in the ocean, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have found. The molecule in question, melatonin, is essential to maintain our daily rhythm, and the European scientists have now discovered that it governs the nightly migration of a plankton species from the surface to deeper waters. The findings, published online today in Cell, indicate that melatonin’s role in controlling daily rhythms probably evolved early in the history of animals, and hold hints to how our sleep patterns may have evolved.
In vertebrates, melatonin is known to play a key role in controlling daily activity patterns – patterns which get thrown out of synch when we fly across time zones, leading to jet lag. But virtually all animals have melatonin. What is its role in other species, and how did it evolve the task of promoting sleep? To find out, Detlev Arendt’s lab at EMBL turned to the marine ragworm Platynereis dumerilii. This worm’s larvae take part in what has been described as the planet’s biggest migration, in terms of biomass: the daily vertical movement of plankton in the ocean. By beating a set of microscopic ‘flippers’ – cilia – arranged in a belt around its midline, the worm larvae are able to migrate toward the sea’s surface every day. They reach the surface at dusk, and then throughout the night they settle back down to deeper waters, where they are sheltered from damaging UV rays at the height of day.
“We found that a group of multitasking cells in the brains of these larvae that sense light also run an internal clock and make melatonin at night.” says Detlev Arendt, who led the research. “So we think that melatonin is the message these cells produce at night to regulate the activity of other neurons that ultimately drive day-night rhythmic behaviour.”
Maria Antonietta Tosches, a postdoc in Arendt’s lab, discovered a group of specialised motor neurons that respond to melatonin. Using modern molecular sensors, she was able to visualise the activity of these neurons in the larva’s brain, and found that it changes radically from day to night. The night-time production of melatonin drives changes in these neurons’ activity, which in turn cause the larva’s cilia to take long pauses from beating. Thanks to these extended pauses, the larva slowly sinks down. During the day, no melatonin is produced, the cilia pause less, and the larva swims upwards.
“When we exposed the larvae to melatonin during the day, they switched towards night-time behaviour,” says Tosches, “it’s as if they were jet lagged.”
The work strongly suggests that the light-sensing, melatonin-producing cells at the heart of this larva’s nightly migration have evolutionary relatives in the human brain. This implies that the cells that control our rhythms of sleep and wakefulness may have first evolved in the ocean, hundreds of millions of years ago, in response to pressure to move away from the sun.
“Step by step we can elucidate the evolutionary origin of key functions of our brain. The fascinating picture emerges that human biology finds its roots in some deeply conserved, fundamental aspects of ocean ecology that dominated life on Earth since ancient evolutionary times,” Arendt concludes.
Enzyme that produces melatonin originated 500 million years ago
An international team of scientists led by National Institutes of Health researchers has traced the likely origin of the enzyme needed to manufacture the hormone melatonin to roughly 500 million years ago.
Their work indicates that this crucial enzyme, which plays an essential role in regulating the body’s internal clock, likely began its role in timekeeping when vertebrates (animals with spinal columns) diverged from their nonvertebrate ancestors.
An understanding of the enzyme’s function before and after the divergence may contribute to an understanding of such melatonin-related conditions as seasonal affective disorder, jet lag, and to the understanding of disorders involving vision.
The findings provide strong support for the theory that the time-keeping enzyme originated to remove toxic compounds from the eye and then gradually morphed into the master switch for controlling the body’s 24-hour cyclic changes in function.
The researchers isolated a second, nonvertebrate form of the enzyme from sharks and other contemporary animals thought to resemble the prototypical early vertebrates that lived 500 million years ago.
The study, published online in PNAS, was conducted by senior author David C. Klein, Ph.D., Chief of the Section on Neuroendocrinology in the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and colleagues at NIH, and at institutions in France, Norway, and Japan.
Melatonin is a key hormone that regulates the body’s day and night cycle. Dr. Klein explained that it is manufactured in the brain’s pineal gland and is found in small amounts in the retina of the eye. Melatonin is produced from the hormone serotonin, the end result of a multistep sequence of chemical reactions. The next-to-last step in the assembly process consists of attaching a small molecule — the acetyl group — to the nearly finished melatonin molecule. This step is performed by an enzyme called arylalkylamine N-acetyltransferase, or AANAT.
Because of its key role in producing the body clock-regulating melatonin, AANAT is often referred to as the timezyme, Dr. Klein added.
The form of AANAT found in vertebrates occurs in the brain’s pineal gland and, in small amounts, in the retina. Another form of the enzyme, termed nonvertebrate AANAT, has been found only in other forms of life, such as bacteria, plants and insects.
“Nonvertebrate AANAT appears to detoxify a broad range of potentially toxic chemicals,” Dr. Klein said. “In contrast, vertebrate AANAT is highly specialized for adding an acetyl group to melatonin. The two are as different from each another as a Ferrari is from a Model-T Ford, considering the speed of the reaction and how fast it can be turned on and off.”
In 2004, Dr. Klein and his coworkers published a theory that melatonin was at first a kind of cellular waste, a by-product created in cells of the eye when normally toxic substances were rendered harmless. Because melatonin accumulated at night, the ancestors of today’s vertebrates became dependent on melatonin as a signal of darkness. As the need for greater quantities of melatonin grew, the pineal gland developed as a structure separate from the eyes, to keep serotonin and other toxic substances needed to make melatonin away from sensitive eye tissue.
“The pineal glands of birds and reptiles can detect light,” Dr. Klein said. “And the retinas of human beings and other species also make melatonin. So it would appear that both tissues evolved from a common, ancestral, light-detecting tissue.”
Before the current study, the researchers lacked proof of their theory, particularly in regard to the question of how the vertebrate form of the enzyme originated because it did not appear to exist in non-vertebrates and had been found only in bony fishes, reptiles, birds, and mammals — all of which lacked the non-vertebrate form.
The first evidence of how the vertebrate form of the enzyme originated came when study co-author Steven L. Coon, also of NICHD, discovered genes for the nonvertebrate and vertebrate forms of AANAT in genomic sequences from the elephant shark, considered to be a living representative of early vertebrates.
This finding indicated that the vertebrate form of AANAT may have resulted after a phenomenon known as gene duplication, Dr. Klein said. Gene duplication, he added, typically results from any of a number of genetic mishaps during cell division. Instead of one copy of a gene resulting from the process, an additional copy results, so that there are two versions of a gene where only one existed previously. The phenomenon is thought to be a major factor influencing evolutionary change.
The researchers theorized that following duplication, one form of AANAT remained unchanged and the other gradually evolved into the vertebrate form. Dr. Klein said that at some point after vertebrate AANAT developed, vertebrates appear to have stopped making the nonvertebrate form, perhaps because it was no longer needed or because its function was replaced by a similar enzyme.
Before the researchers could continue, they needed to confirm their finding, to rule out that the nonvertebrate AANAT they found didn’t result from accidental contamination with bacteria or some other organism. The NICHD researchers sought assistance from other research teams around the world. DNA from Mediterranean sharks and sea lampreys was obtained via fishermen’s catches by Jack Falcon of the Arago Laboratory, a marine biology facility that is part of the CNRS and the Pierre and Marie Curie University in France. Samples from a close relative of the elephant shark — the ratfish — were provided by Even-Jorgensen at the Arctic University of Norway. Finally, Susumo Hyodo of the University of Tokyo contributed samples from elephant sharks he collected off the coast of Australia.
Next, the Hyodo and Falcon groups isolated RNA from the retinas and pineal glands of the animals. RNA is used to direct the assembly of amino acids into proteins. From these RNA sequences, it was possible to assemble working versions of AANAT molecules — both the vertebrate and nonvertebrate forms.
The sequences of the proteins encoded by the AANAT genes were analyzed by Eugene Koonin and Yuri Wolf of the National Library of Medicine using computer techniques designed to study evolution. Peter Steinbach, of NIH’s Center for Information Technology, examined the three-dimensional structures of nonvertebrate and vertebrate AANAT in the study animals and determined that the two forms of the enzyme likely had a common ancestor.
Taken together, their results provide evidence for the hypothesis that nonvertebrate AANAT resulted from duplication of the non-vertebrate AANAT gene about 500 million years ago and that following this event one copy of the duplicated gene eventually changed into the gene for vertebrate AANAT.
In addition to providing information on the origin of melatonin and the evolution of AANAT, the findings also have implications for research on disorders affecting vision. Vertebrate AANAT and melatonin are found in small amounts in the eyes of humans and other vertebrates. Although they may play a role in detoxifying compounds, it is also reasonable to consider that this detoxifying function is shared with other enzymes.
“It’s possible that a malfunction in these other enzymes might lead to an accumulation of chemicals known as arylalkamines — in the same family as serotonin — and this might contribute to eye disease,” Dr. Klein said. “Consequently, research into how these enzymes function might lead to therapies to protect vision.”
Bad night’s sleep? The moon could be to blame
Many people complain about poor sleep around the full moon, and now a report appearing in Current Biology, a Cell Press publication, on July 25 offers some of the first convincing scientific evidence to suggest that this really is true. The findings add to evidence that humans—despite the comforts of our civilized world—still respond to the geophysical rhythms of the moon, driven by a circalunar clock.
"The lunar cycle seems to influence human sleep, even when one does not ‘see’ the moon and is not aware of the actual moon phase," says Christian Cajochen of the Psychiatric Hospital of the University of Basel.
In the new study, the researchers studied 33 volunteers in two age groups in the lab while they slept. Their brain patterns were monitored while sleeping, along with eye movements and hormone secretions.
The data show that around the full moon, brain activity related to deep sleep dropped by 30 percent. People also took five minutes longer to fall asleep, and they slept for twenty minutes less time overall. Study participants felt as though their sleep was poorer when the moon was full, and they showed diminished levels of melatonin, a hormone known to regulate sleep and wake cycles.
"This is the first reliable evidence that a lunar rhythm can modulate sleep structure in humans when measured under the highly controlled conditions of a circadian laboratory study protocol without time cues," the researchers say.
Cajochen adds that this circalunar rhythm might be a relic from a past in which the moon could have synchronized human behaviors for reproductive or other purposes, much as it does in other animals. Today, the moon’s hold over us is usually masked by the influence of electrical lighting and other aspects of modern life.
The researchers say it would be interesting to look more deeply into the anatomical location of the circalunar clock and its molecular and neuronal underpinnings. And, they say, it could turn out that the moon has power over other aspects of our behavior as well, such as our cognitive performance and our moods.
Melatonin delays ALS symptom onset and death in mice
Melatonin injections delayed symptom onset and reduced mortality in a mouse model of the neurodegenerative condition amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, according to a new study by researchers at the University of Pittsburgh School of Medicine. In a report published online ahead of print in the journal Neurobiology of Disease, the team revealed that receptors for melatonin are found in the nerve cells, a finding that could launch novel therapeutic approaches.
Annually about 5,000 people are diagnosed with ALS, which is characterized by progressive muscle weakness and eventual death due to the failure of respiratory muscles, said senior investigator Robert Friedlander, M.D., UPMC Endowed Professor of neurosurgery and neurobiology and chair, Department of Neurological Surgery, Pitt School of Medicine. But the causes of the condition are not well understood, thwarting development of a cure or even effective treatments.
Melatonin is a naturally occurring hormone that is best known for its role in sleep regulation. After screening more than a thousand FDA-approved drugs several years ago, the research team determined that melatonin is a powerful antioxidant that blocks the release of enzymes that activate apoptosis, or programmed cell death.
"Our experiments show for the first time that a lack of melatonin and melatonin receptor 1, or MT1, is associated with the progression of ALS," Dr. Friedlander said. "We saw similar results in a Huntington’s disease model in an earlier project, suggesting similar biochemical pathways are disrupted in these challenging neurologic diseases."
Hoping to stop neuron death in ALS just as they did in Huntington’s, the research team treated mice bred to have an ALS-like disease with injections of melatonin or with a placebo. Compared to untreated animals, the melatonin group developed symptoms later, survived longer, and had less degeneration of motor neurons in the spinal cord.
"Much more work has to be done to unravel these mechanisms before human trials of melatonin or a drug akin to it can be conducted to determine its usefulness as an ALS treatment," Dr. Friedlander said. "I suspect that a combination of agents that act on these pathways will be needed to make headway with this devastating disease."
(Source: eurekalert.org)
Red Light Increases Alertness During “Post-Lunch Dip”
Acute or chronic sleep deprivation resulting in increased feelings of fatigue is one of the leading causes of workplace incidents and related injuries. More incidents and performance failures, such as automobile accidents, occur in the mid-afternoon hours known as the “post-lunch dip.” The post-lunch dip typically occurs from 2-4 p.m., or about 16-18 hours after an individual’s bedtime from the previous night.
A new study from the Lighting Research Center (LRC) at Rensselaer Polytechnic Institute shows that exposure to certain wavelengths and levels of light has the potential to increase alertness during the post-lunch dip. The research was a collaboration between Mariana Figueiro, LRC Light and Health Program director and associate professor at Rensselaer, and LRC doctoral student Levent Sahin. Results of the study titled “Alerting effects of short-wavelength (blue) and long-wavelength (red) lights in the afternoon,” were recently published in Physiology & Behavior journal.
The collaboration between Figueiro and Sahin lays the groundwork for the possible use of tailored light exposures as a non-pharmacological intervention to increase alertness during the daytime. Figueiro has previously conducted studies that show that light has the potential to increase alertness at night. Exposure to more than 2500 lux of white light at night increases performance, elevates core body temperature, and increases heart rate.
In most studies to date, the alerting effects of light have been linked to its ability to suppress melatonin. However, results from another study led by Figueiro demonstrate that acute melatonin suppression is not needed for light to affect alertness during the nighttime. They showed that both short-wavelength (blue) and long-wavelength (red) lights increased measures of alertness but only short-wavelength light suppressed melatonin. Melatonin levels are typically lower during the daytime, and higher at night.
Figueiro and Sahin hypothesized that if light can impact alertness via pathways other than melatonin suppression, then certain wavelengths and levels of light might also increase alertness during the middle of the afternoon, close to the post-lunch dip hours.
During the study conducted at the LRC, participants experienced two experimental lighting conditions in addition to darkness. Long-wavelength “red” light (λmax = 630 nanometers) and short-wavelength “blue” light (λmax = 470 nanometers) were delivered to the corneas of each participant by arrays of light emitting diodes (LEDs) placed in 60 × 60 × 60 cm light boxes. Participant alertness was measured by electroencephalogram (EEG) and subjective sleepiness (KSS scale).
The team found that, compared to remaining in darkness, exposure to red light in the middle of the afternoon significantly reduces power in the alpha, alpha theta, and theta ranges. Because high power in these frequency ranges has been associated with sleepiness, these results suggest that red light positively affects measures of alertness not only at night, but also during the day. Red light also seemed to be a more potent stimulus for modulating brain activities associated with daytime alertness than blue light, although they did not find any significant differences in measures of alertness after exposure to red and blue lights. This suggests that blue light, especially higher levels of blue light, could still increase alertness in the afternoon. It appears that melatonin suppression is not needed for light to have an impact on objective measures of alertness.
“Our study suggests that photoreceptors other than the intrinsically photosensitive retinal ganglion cells respond to light for the arousal system,” said Figueiro. “Future research should look into the spectral sensitivity of alertness and how it changes over the course of 24 hours.”
Sahin, who has more than 10 years of experience in railway engineering, was interested in this study from a transportation safety perspective, and what the results could mean to the transportation industry. “Safety is a prerequisite and one of the most important quality indicators in the transportation industry,” said Sahin. “Our recent findings provided the scientifically valid underpinnings in approaching fatigue related safety problems in 24 hour transportation operations.”
From the present results, it is not possible to determine the underlying mechanisms contributing to light-induced changes in alertness because the optical radiation incident on the retina has multiple effects on brain activity through parallel neural pathways. According to Figueiro, that is an area that she would like to explore in future research.
Making headway on beta-blockers and sleep
Researchers at Brigham and Women’s Hospital have found that melatonin supplementation significantly improved sleep in hypertensive patients taking beta-blockers
Over 20 million people in the United States take beta-blockers, a medication commonly prescribed for cardiovascular issues, anxiety, hypertension and more. Many of these same people also have trouble sleeping, a side effect possibly related to the fact that these medications suppress night-time melatonin production. Researchers at Brigham and Women’s Hospital (BWH) have found that melatonin supplementation significantly improved sleep in hypertensive patients taking beta-blockers.
The study will be electronically published on September 28, 2012 and will be published in the October print issue of SLEEP (Title: A mechanism for upper airway stability during slow wave sleep).
"Beta-blockers have long been associated with sleep disturbances, yet until now, there have been no clinical studies that tested whether melatonin supplementation can improve sleep in these patients," explained Frank Scheer, PhD, MSc, an associate neuroscientist at BWH, and principal investigator on this study. "We found that melatonin supplements significantly improved sleep."
The research team analyzed 16 hypertensive patients who regularly took beta-blockers as treatment for their hypertension. The study participants were given either a melatonin supplement or placebo to take each night before bed. To avoid bias, neither the participants nor the researchers knew which pill they were taking. During the three week study, the participants spent two separate four-day visits in lab. While in the lab, the researchers assessed the participants’ sleep patterns and found a 37-minute increase in the amount of sleep in the participants who received the melatonin supplement compared to those who received placebo. They also found an eight percent improvement of sleep efficiency and a 41 minute increase in the time spent in Stage 2 sleep, without a decrease in slow wave sleep or REM sleep.
"Over the course of three weeks, none of the study participants taking the melatonin showed any of the adverse effects that are often observed with other, classic sleep aids. There were also no signs of ‘rebound insomnia’ after the participants stopped taking the drug," explained Scheer, who is also an assistant professor of Medicine at Harvard Medical School. "In fact, melatonin had a positive carry-over effect on sleep even after the participants had stopped taking the drug."
The researchers caution that while this data is promising for hypertensive patients taking beta-blockers, more research is needed to determine whether patients taking beta-blockers for causes other than hypertension could also benefit from melatonin supplementation.
(Source: eurekalert.org)
Melatonin and exercise work against Alzheimer’s in mice
Different anti-aging treatments work together and add years of life
The combination of two neuroprotective therapies, voluntary physical exercise, and the daily intake of melatonin has been shown to have a synergistic effect against brain deterioration in rodents with three different mutations of Alzheimer’s disease.
A study carried out by a group of researchers from the Barcelona Biomedical Research Institute (IIBB), in collaboration with the University of Granada and the Autonomous University of Barcelona, shows the combined effect of neuroprotective therapies against Alzheimer’s in mice.
Daily voluntary exercise and daily intake of melatonin, both of which are known for the effects they have in regulating circadian rhythm, show a synergistic effect against brain deterioration in the 3xTg-AD mouse, which has three mutations of Alzheimer’s disease.
"For years we have known that the combination of different anti-aging therapies such as physical exercise, a Mediterranean diet, and not smoking adds years to one’s life," Coral Sanfeliu, from the IIBB, explains to SINC. "Now it seems that melatonin, the sleep hormone, also has important anti-aging effects".
The experts analysed the combined effect of sport and melatonin in 3xTg-AD mice which were experiencing an initial phase of Alzheimer’s and presented learning difficulties and changes in behaviour such as anxiety and apathy.
The mice were divided into one control group and three other groups which would undergo different treatments: exercise –unrestricted use of a running wheel–, melatonin –a dose equivalent to 10 mg per kg of body weight–, and a combination of melatonin and voluntary physical exercise. In addition, a reference group of mice were included which presented no mutations of the disease.
"After six months, the state of the mice undergoing treatment was closer to that of the mice with no mutations than to their own initial pathological state. From this we can say that the disease has significantly regressed," Sanfeliu states.
The results, which were published in the journal Neurobiology of Aging, show a general improvement in behaviour, learning, and memory with the three treatments.
These procedures also protected the brain tissue from oxidative stress and provided good levels of protection from excesses of amyloid beta peptide and hyperphosphorylated TAU protein caused by the mutations. In the case of the mitochondria, the combined effect resulted in an increase in the analysed indicators of improved performance which were not observed independently.
(Source: eurekalert.org)
Dark matter DNA active in brain during day — night cycle
NIH study of rats shows DNA regions thought inactive highly involved in body’s clock
Long stretches of DNA once considered inert dark matter appear to be uniquely active in a part of the brain known to control the body’s 24-hour cycle, according to researchers at the National Institutes of Health.
Working with material from rat brains, the researchers found some expanses of DNA contained the information that generate biologically active molecules. The levels of these molecules rose and fell, in synchrony with 24-hour cycles of light and darkness. Activity of some of the molecules peaked at night and diminished during the day, while the remainder peaked during the day and diminished during the night.
What Time Is It on Your Circadian Clock?
Are you a morning lark or a night owl? Scientists use that simplified categorization to explain that different people have different internal body clocks, commonly called circadian clocks. Sleep-wake cycles, digestive activities, and many other physiological processes are controlled by these clocks. In recent years, researchers have found that internal body clocks can also affect how patients react to drugs. For example, timing a course of chemotherapy to the internal body time of cancer patients can improve treatment efficacy and reduce side effects.
Round the clock. Tracking the levels of 50 hormones and amino acids in blood samples (shown by ribbons) reveals a body’s internal time. Credit: PNAS
But physicians have not been able to exploit these findings because determining internal body time is, well, time consuming. It’s also cumbersome. The most established and reliable method requires taking blood samples from a patient hourly and tracking levels of the hormone melatonin, which previous research has tied closely to internal body time.
Now a Japanese group has come up with an alternative method of determining internal body time by constructing what it calls a molecular timetable based on levels in blood samples of more than 50 metabolites—hormones and amino acids—that result from biological activity. The researchers established a molecular timetable based on samples from three subjects and validated it using the conventional melatonin measurement. They then used that timetable to determine the internal body times of other subjects by checking the levels of the metabolites in just two blood samples from each subject per day.
Having such a timetable could allow doctors to synchronize drug delivery to internal body time, the team reports online today in the Proceedings of the National Academy of Sciences. “Usually personalized medicine is focusing on genetic differences, but there are also temporal differences [among patients]. That will be the next step in personalized medicine,” says systems biologist Hiroki Ueda of the RIKEN Center for Developmental Biology in Kobe, Japan, who heads the research group.
"In principle, the method holds great promise as a way of replacing the cumbersome melatonin assay," says Steven Brown, a molecular biologist at the University of Zurich in Switzerland. "The authors show in a small-scale, well-controlled experiment that they are able to predict internal body time within a precision frame of 3 hours," says Urs Albrecht of the University of Fribourg in Switzerland. Both researchers say further work will be necessary to make the technique more practical and more widely applicable, and Ueda agrees. The experimental subjects were all young men, and different molecular timetables are likely needed for women and for people of different ages. He would also like to improve the precision and make it reliable with just one blood sample per day.
Source: ScienceNOW