Histamine and Circadian Rhythms

The daily cycles of light and darkness last approximately 24 hours, corresponding to the time it takes for the Earth to complete one full rotation on its axis. The vast majority of organisms adjust to these cycles, which is reflected in their physical, psychological, and behavioral functions thanks to the circadian rhythm. This rhythm is regulated by the internal circadian clock of each organism.

The adaptation of the circadian clock to daily cycles is achieved through various factors such as temperature changes, metabolic cycles, and feeding, as well as neural or hormonal stimuli.

These factors are known as Zeitgebers, which comes from the German “synchronizer.” Zeitgebers synchronize the circadian clock with a specific time of day, affecting both the functions that will be carried out, as well as the genes and proteins that will be activated at each moment.

The circadian clock is molecularly composed of a machinery of proteins that are activated throughout the day, and regulate each other to maintain their own balance. Instead of a simple process, there is a complex regulatory network that allows the circadian clock to perform its functions at the right time and maintain the integrity of each organ and cell.

Central Clock and Peripheral Clocks and Biological Rhythms

Throughout evolution, our body has developed both central and peripheral molecular clocks, located in organs such as the liver, intestine, or muscle. These clocks synchronize based on external signals, such as light, physical activity, and primarily food, affecting gene expression and hormone secretion.

The main zeitgeber for the central clock, located in the suprachiasmatic nucleus in the hypothalamus of our brain, is light. While for peripheral clocks (in the rest of the body), it is food.

Respecting and understanding the natural physiological fluctuations of the body can contribute to having a healthier organism.

In developed countries, modern habits, which often do not follow the natural rhythms of light-darkness and meal-fasting, can be a determining factor in the onset of metabolic diseases such as cancer or diabetes.

Disruption of the circadian clock can affect health

If the clock is out of control, organs and cells lose their ability to anticipate and prepare for their tasks.

This lack of control can worsen any disease. The accumulation of damage in the body occurs when it is not prepared to carry out efficient repair while continuing its usual tasks.

Relation of histamine with wake-sleep cycles

Recent studies conclude that the quantity and activity of mast cells are modulated by circadian rhythms and factors such as light and feeding, which can also synchronize or desynchronize our clocks.

Mast cells are associated with the regulation of immunity and inflammation through the release of important inflammatory mediators, including histamine.

This can bind to their receptors. And it has four, of which two, H1 and H3R, are expressed in the brain.

Among other functions in the brain, histamine can influence the wake-sleep cycle and therefore also its disorders.

Wake and sleep states are complex processes that occur thanks to coordinated neurochemical changes in neurotransmitters and neuromodulators, such as acetylcholine, glutamate, gamma-aminobutyric acid, dopamine, serotonin, norepinephrine, histamine, hypocretin, melanin-concentrating hormone, adenosine, and melatonin.

Brain histaminergic neurons play an important role in arousal and maintaining wakefulness.

Pham L. et al., (2021)

Melatonin and histamine the necessary balance

Melatonin is released into the cerebrospinal fluid, at night with very high levels, while during the day it is released at very low levels.

It is key in the regulation of circadian rhythms and the functioning of other hormones. In the previous image, the two receptors MT1 and MT2 are seen. The binding of melatonin to these receptors leads to a decrease in the activation, proliferation, and differentiation of mast cells.

Melatonin and histamine are two important neuromodulators involved in the regulation of circadian rhythms through NF-κB, a common key factor.

Therefore, a good release of melatonin could favor processes that involve mast cell dysregulation.

Although more research is needed regarding the link between melatonin, histamine, and circadian rhythms, in the meantime, we can begin to apply strategies where there is more solid evidence to improve the synchronization of our clocks. Exposure to light and meal timings.

Harmful habits for our circadian rhythm and histamine balance

When we think of chronodisruptive behaviors, those that disrupt our circadian rhythms, the first thing that comes to mind are habits like dining late, exercising in nighttime slots, or watching television until late at night.

If we analyze each of these habits separately, we can conclude that dining late affects our metabolism because during the night we are less sensitive to insulin, which decreases our glucose tolerance.

High-intensity exercise at night could alter sleep by releasing stress hormones. And besides, going to bed late can reduce the quality and duration of sleep. However, what is probably underestimated is that behind these habits is a key factor that interferes with the mechanisms that regulate our circadian rhythms: light.

Given that exposure to bright artificial light and light from electronic devices at night is common worldwide and that our body needs darkness to carry out certain physiological processes such as melatonin release, it has been studied that exposure to blue and bright artificial light before and during nocturnal sleep can have negative consequences for health.

For example, in a study by Gil-Lozano et al., (2022) showed that a complete night of sleep deprivation with exposure to light increased insulin resistance and disrupted normal profiles of melatonin and cortisol production.

Although technological progress has benefited our quality of life, its excessive use can have negative consequences. Exposing oneself to artificial light at night can affect our metabolism and increase the risk of obesity and type II diabetes.

Therefore, it is important to adopt strategies that minimize the possibility of sleeping with illumination to improve our health: use blue light-blocking glasses for screens, and in the bedroom, lower the blinds or use a sleep mask to have absolute darkness when sleeping.

On the other hand, intake schedules could also deregulate our clocks.

Dining close to daylight hours and lengthening nighttime fasting is what our physiology expects from us, as it turns out to be a period where our body instead of digesting will allocate energy to cell recycling and repair.

Adapting our eating habits during the day and avoiding eating at least two hours before going to bed will give rest to the digestive system and permission to the immune system to perform its functions.

We must be aware of the importance of sleep and chronoregulation in our health, and that probably good synchronization of our clocks (central and peripheral) could have a positive impact on people with mast cell degranulation pathologies, and therefore with histamine problems.

REFERENCES


 

  • Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes & development. 2000 Dec 1;14(23):2950-61.
  • Carroll, R. G., Timmons, G. A., Cervantes-Silva, M. P., Kennedy, O. D., & Curtis, A. M. (2019). Immunometabolism around the Clock. Trends in molecular medicine.
  • Brown SA, Zumbrunn G, Fleury-Olela F, Preitner N, Schibler U. Rhythms of mammalian body temperature can sustain peripheral circadian clocks. Current Biology. 2002 Sep 17;12(18):1574-83.
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  • Linh Pham, Leonardo Baiocchi, Lindsey Kennedy, Keisaku Sato, Vik Meadows, Fanyin Meng, Chiung-Kuei Huang, Debjyoti Kundu, Tianhao Zhou, Lixian Chen, Gianfranco Alpini, Heather Francis. The interplay between mast cells, pineal gland, and circadian rhythm: Links between histamine, melatonin, and inflammatory mediators. J Pineal Res. 2021 March; 70(2).
  • Welz PS, Benitah SA. Molecular connections between circadian clocks and aging. Journal of molecular biology. 2020 May 29;432(12):3661-79.
  • García-Gaytán AC, Miranda-Anaya M, Turrubiate I, López-De Portugal L, Bocanegra-Botello GN, López-Islas A, et al. Synchronization of the circadian clock by time-restricted feeding with progressive increasing calorie intake. Resemblances and differences regarding a sustained hypocaloric restriction. Sci Rep [Internet]. 2020;10(1):10036.
  • Lancet T. Waking up to the importance of sleep. The Lancet [Internet]. 2022 Sep 24;400(10357):973.

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