https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151498/

Melatonin Effects on the Brain, Sleep, Mitochondria, Vision/Eyes and Hearing (Part 1)

Melatonin is important for normal brain and eye function. It can also reduce oxidative stress and improve sleep quality. Read more below to learn about its beneficial effects.

Introduction

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151498/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151498/

Melatonin is an ancient and highly conserved substance derived from a key amino acid, tryptophan (R).

It is present in every type of living being from bacteria and plants to animals. Throughout evolution, it has acquired a lot of different functions and has become indispensable in humans.

Here are several of its main functions:

  • Influences the day-and – night cycle;
  • aids the immune system;
  • helps the function of sight;
  • reduces oxidative stress;
  • promotes sleep;
  • controls many events inside the cell, including synthesis of important molecules;
  • and protects against radiation.

A part of the brain, the pineal gland, makes melatonin. The quantity of melatonin in the blood depends on the time of the day. At night there is 10 to 15 times more melatonin in the blood that in the day, which helps people sleep (R).

It is also made by many other organs in the body, and especially in the gut (R).

If the sleep is interrupted by switching on the light at night, it can decrease melatonin concentrations. Its quantity also decreases with age (R).

Melatonin acts through interacting with two receptor proteins, MT1 and MT2 (R).

Studies in mice have shown that interaction of melatonin with those receptors can lead to opposing results (R, R2).

MT1 and MT2 receptors control different stages of sleep: MT1 controls deep sleep, or REM sleep and MT2 controls the stages of sleep preceding dreaming (R).

Health Benefits of Melatonin

1) Melatonin Protects Cells and their Mitochondria

Mitochondria are the part of the cell that generates energy. They have their own DNA. As energy factories, they are crucial for survival. The nucleus and mitochondria are the areas that have the most melatonin (R).

Energy production by mitochondria leads to the creation of harmful molecules that are referred to as “molecular terrorists”. Those terrorists are usually made from oxygen and nitrogen and are referred as reactive oxygen species (ROS) and reactive nitrogen species (RNS) (R).

Their main danger is that they damage mitochondrial DNA and proteins, rendering them unable to produce energy. Also, as the mitochondrial walls become destroyed due to harmful molecules, they begin to leak potential poisons into the cell, spreading harm wider and leading to cell death (R).

Melatonin is able to bind to such molecules, acting as a scavenger. It performs this task through several reactions, transforming into new molecules along the way (R).

Most of the molecules that melatonin transform into retaining the ability to bind harmful oxygen and nitrogen species which makes melatonin and its products highly effective protection (R).

A single molecule of melatonin may neutralize up to ten toxic reactants (R).

Besides directly binding harmful substances, melatonin activates other molecules that help clean the cell and bloodstream from harmful molecules (R).

It also blocks a protein called nitric oxide synthase that produces reactive nitrogen species (R).

Pharmacologists try to make synthetic analogs of melatonin and melatonin-related molecules for blocking this protein because it is often active in neural diseases ranging from stroke to Alzheimer’s and Parkinson’s disease (R).

It also activates γ-glutamylcysteine synthase (γ-GCS), a protein that blocks the production of glutathione, a potentially damaging molecule (R).

Moreover, melatonin and a molecule directly made from it, such as AMK (N1-acetyl-5-methoxykynuramine) has an activity that prevents the formation of most damaging molecules (R).

2) Melatonin Is Good For Your Brain

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As nerve cells usually possess a very big quantity of mitochondria and require the most energy and as melatonin is essentially a hormone for nerves, it helps the brain in many instances.

Melatonin can help in brain trauma (R).

Treatment of rats with melatonin after brain injury helps reduce the subsequent swelling of various brain regions (R).

Melatonin activates brain-derived neurotrophic factor (BDNF), a protein responsible for nerve – cells well-being (R).

It prevents nerve cell death due to its ability to interfere with proteins that initiate the event (R).

On mice models of stroke, melatonin was able to block the release of death-activating protein cytochrome c from mitochondria, which effectively prevented cell death as a result of the injury (R).

On another rat model of a stroke, melatonin blocks the activity of several proteins such as IL-1β, TNF-α, BAD, and BAX that initiate inflammation and death of the nerve cells after the artery leading to the brain gets blocked (R).

It also increased the levels of proteins that prevent cell death (R).

It also strengthens the barrier between brain and the blood (R).

On mouse nerve cells culture, melatonin prevents nerve cell death caused by amyloid beta25-35, a substance that causes a condition similar to Alzheimer’s disease (R).

In amyotrophic lateral sclerosis (ALS), the nerve cells responsible for movement begin to die and this disease is usually fatal. According to experiments on mouse models, melatonin can help relieve symptoms of ALS. It prevents the death of those cells and slows the disease progress in mice (R).

Another way of preventing cell death through the influence of melatonin is its ability to repair damaged mitochondria directly, thus preventing leakage of damaging molecules (R).

3) Melatonin Alleviates Nervous Disorder Symptoms

Melatonin can help alleviate symptoms similar to Alzheimer′s and Parkinson′s disease in mice and rats (R).

In humans, both MT1 and MT2 levels are low in elderly patients with Alzheimer’s (R).

The decrease in melatonin activity and synthesis may explain in part the disruption of sleep and problems with processing information observed in Alzheimer patients (R).

The treatment of elderly patients with Alzheimer`s disease (AD) with bright light and melatonin improved their sleep and overall rest (R).

A similar study carried out for several years in Netherlands showed that combined treatment of AD patient with bright light and melatonin has been beneficial both for rest and mental problems (R).

The development of Parkinson’s disease also disrupts sleep (R).

There are several studies that show melatonin to improve sleep in patients with this condition, but it does not improve other associated problems (R, R2).

4) Melatonin Is Good For Treating Sleep Disorders

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Melatonin controls sleep-awake cycle (R).

It was also noted that in patients with insomnia, melatonin concentration is significantly lower compared to people with normal sleep ability (R)

Melatonin induces sleep through two melatonin receptors, melatonin 1a, and melatonin 1b receptors (R).

Melatonin helps patients to go to sleep quicker, sleep longer and deeper (R).

Some works suggest that melatonin itself is not effective in some types of sleep disorders, though it does improve sleep quality (R).

It helps patients discontinue therapy with benzodiazepines, a class of drugs usually prescribed for anxiety and insomnia. Benzodiazepines can have potential side effects and make patients addicted. Also, withdrawal of such therapy can be very hard for the patient, leading to sleep deprivation and anxiety (R).

Melatonin supplementation helps patients reduce their dependence on drugs, without major side effects (R).

Melatonin can also be a safe option for children with autism disorders and ADHD. In the case of ADHD, administration of melatonin has helped children to go to sleep an hour earlier in average (R).

5) Melatonin Can Help Against Some Poisons

Due to such diverse properties, melatonin is able to downplay the effects of several poisons that directly affect the mitochondria (R).

It is protective against rotenone – a poison that can mimic Parkinson’s disease in rats (R).

MPTP is a poison dangerous to nerve cells that deprive them of energy and leads to their death. This substance disrupts the activity of a crucial mitochondrial protein – complex I. It can be accidentally ingested by drug addicts and lead to severe neurological symptoms similar to Parkinson’s disease (R).

Melatonin prevented the damage to the cell fat molecules in many regions of the brain in mice after MPTP injection. It also made many important proteins return to normal state and protected DNA in the mitochondria from damage (R).

Melatonin is also protective against 3-NPA. 3-NPA is a toxin from fungi that can infect sugarcane. There were cases in children who ate contaminated sugar cane and developed a condition similar to Huntington’s disease, and their movements were impaired (R).

In rats affected by this poison, melatonin prevented nerve cell loss, corrected damaging behavior, prevented protein and fat molecules damage and restored levels of dopamine – a molecule responsible for controlling movement and mood (R).

Melatonin can be helpful even against cyanide (R, R2).

Cyanide is a highly lethal poison that causes the massive death of nerve cells and seizures that can eventually lead to death. It also damages the nerve cells’ mitochondria. In mice that received cyanide injections, previous treatment with melatonin can reduce the severity of seizures caused by the poison (R).

It also protects the damage to mitochondrial DNA caused by potassium cyanide in mice and in culture (R).

6) Melatonin Can Help Calm You Down

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Melatonin also has a use in the treatment of anxiety and depression.

Depression and other mood disorders are often coupled with sleep disturbances and require agents that should have the ability to calm the patient down.vDrugs that can activate and bind MT2 receptors can be potential therapeutic agents for such conditions (R).

Changes in day-and-night concentrations of melatonin can be markers of severe depression (R).

Melatonin helps with sleep regulation and depression in patients with delayed sleep phase syndrome (R).

In rats, melatonin can alleviate depression induced by chronic stress and significantly change the dynamics of several parameters in the brain of these animals (R).

Treatment with melatonin of breast cancer patients reduced the risk of development of depression (R).

Melatonin synthesis is also disrupted in in patients with bipolar disorder. Melatonin and drug agents interacting with MT receptors, like ramelteon and tasimelteon can be a beneficial therapy for bipolar disorder as well (R).

As bipolar disorder is also associated with sleep and mood deregulation, melatonin can improve the condition in patients with this problem (R).

7) Melatonin Is Important For The Eyes

The cells of the eye, especially the retina, make melatonin (R).

Light influences its production, and the cells that react to light produce it.  The more light there is the less melatonin the cells in the eye produce (R).

Disruption of MT receptors leads to the death of cones – cells in the eye that help the eye to discern color (R).

Melatonin is also important for normal eye development. For example, mice that lacked one of the melatonin receptors – MT1 – had a decrease in specific nerve cells content crucial for vision (R).

Additionally, it can decrease elevated pressure in the eye in humans. Moreover, removal of MT1 in mice results in an increase in the pressure inside the eye and death of nerve cells (R).

The disturbances in melatonin functioning may be one of the causes of glaucoma (R).

Melatonin and 5-MCA-NAT are promising agents for treating glaucoma – an eye condition caused by elevated pressure (R).

It was also shown to protect human cells that make eye pigment from cell death (R).

Melatonin also prevents the death of nerve cells in an experimental model of optic neuritis in rats. Optic neuritis is a disease that causes the death of optic nerve cells responsible for vision (R).

Also, it is beneficial in refractory central serous chorioretinopathy –  a condition that affects the eyes of diabetic patients (R).

A supplementation with melatonin drops in infancy and in the elderly can potentially be beneficial for eye protection (R).

8) Melatonin Can Relieve Noises in the Ear

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Tinnitus is the unexplained noise in the ears that affects many people: elderly, those with a hearing disability or as a result of certain drugs (R, R2).

Melatonin was 150 times more effective compared with other drugs that treat tinnitus. It decreased the symptoms of the condition (R).

In elderly with tinnitus, melatonin levels are very low. This may indicate that its levels are connected with normal ear activity (R).

Melatonin Part 2

Technical

  • Moreover, there is about 100 times more MT in the gut than blood (R).
  • For example, mice that had their MT1 receptors knocked out not only had severe sleep disturbances, they also had melancholic-like behavior similar to depression in humans (R).
  • In mouse mitochondria, directly incubating mitochondria with MT improves various parameters of their activity. It also improves production of the main energy molecule – ATP (R).
  • There are a lot of cells that have those types of receptors in an area of the brain called suprachiasmatic nucleus or SCN that is responsible for controlling day-night cycles and sleep (R).
  • The MT2 receptor is also lower in the eyes of Alzheimer’s patients (R).
  • Agomelatine is an MT analogue that is able to activate both MT receptors and in the same time block the 5-HT2c receptor that binds with serotonin (R).
  • It prevents cell death more effectively than other antioxidants, like vitamin E, glutathione, mannitol and vitamin C (R).
  • They are hypnotic agents, as the stages preceding REM sleep are similar to a hypnotic state (R).
  • Recently, several combinational therapies containing melatonin and an agonist of the MT3 receptor, 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT), can decrease eye pressure in rabbits (R).

Caution

Melatonin and bright light can improve the mood and symptoms of Alzheimer’s patients. However, without the additional bright light, it may have a negative effect on the mood of such patients. It may also lead to an increase in aggressive behaviour (R).

In rats, melatonin also helps eliminates harmful oxidative molecules in the nerve cells after brain injury. However, it prolongs coma caused by the trauma (R).

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