Introduction: Multiple evidence suggests that dopamine is involved in regulating sleep: drugs that target the dopamine signaling pathway can effectively regulate wakefulness; elimination of dopamine reduces the duration of REM sleep in mice; and dopamine receptor type 2 (Drd2) agonists promote RAPID EYE movement sleep. Therefore, dopamine is likely to be a potential new drug target for the treatment of sleep disorders.
The report of the Nineteenth National Congress put forward the "Healthy China" development strategy, the National Health Commission issued the "Healthy China Action (2019-2030)" in 2019, which included sleep health into the main action indicators, and officially proposed China's sleep duration standard, known as the "sleep national standard", the average daily sleep time of adults is 7-8 hours, and the sleep time of primary school students, junior high school students, and high school birthdays is greater than or equal to 10 hours, 9 hours, and 8 hours, respectively. However, in daily life, the sleep time of the Chinese people has not reached the standard for a long time, and the quality of sleep is worrying. According to the sleep research report of the Chinese Sleep Research Association, more than 300 million people in the mainland have sleep disorders, and sleep health problems need urgent attention.
Secrets of Alternating Sleep Cycles:
Dopamine initiates REM sleep
Recently, the takeshi Sakurai research team at the University of Tsukuba in Japan, relying on the GRAB-DA dopamine fluorescent probe technology, revealed that dopamine acts on neurons expressing the dopamine receptor D2 (Drd2) in the amygdala, which can induce rapid eye movement sleep, indicating that dopamine signaling plays a key role in initiating REM sleep, and provides a neuronal basis for the production of sleep cycles [1]. The research was published in Science under the title "Rapid eye movement sleep isinitiated by basolateral amygdala dopamine signaling in mice" (Figure 1).
Figure 1 Research results (Source: Science)
GRAB-DA is a dopamine fluorescent probe that observes the concentration of dopamine in mice in the lateral amygdala (BLA), accumbenda nucleus (NAc), and lateral region (LHA) of the nuclear hypothalamus (LHA) of the prefrontal cortex (mPFC) during sleep-wake period. Using a dopamine fluorescent probe, the researchers found three dynamic patterns of dopamine during the transition from non-REM sleep to REM sleep in mice (Figure 2):
In the BLA zone, the transition from non-REM sleep to REM sleep, a transient increase in dopamine levels and a decrease during REM sleep;
In NAc, dopamine levels increase during the transition from non-REM sleep to REM sleep, and slightly higher average fluctuations occur during REM sleep;
In the mPFC and LHA regions, during the transition from non-REM sleep to REM sleep, dopamine levels show little change and decrease significantly during REM sleep.
Based on the above results, the researchers interfered with the release of dopamine through optogenetic techniques to monitor the effect of increased dopamine levels in BLA and NAc during non-REM sleep on the sleep-wake state of mice. Through related experiments, the researchers found that:
After light activation of DOP neurons in the BLA region during the non-REM sleep period, mice were briefly induced to enter REM sleep, indicating that the dopamine signaling in the BLA region played an important role in mice entering the REM sleep period.
During non-REM sleep, light inhibits dopamine type 2 receptor (Drd2) positive neurons in the BLA region, prompting mice to briefly enter the REM sleep phase.
Fig. 2 Optogenetic excitation of dopamine in BLA induces REM sleep during non-REM sleep (Source: Science)
In addition, the researchers also found that when the mice were awake, a brief increase in dopamine levels in the BLA induced the occurrence of cataplexy. Thus, this study shows the important role of dopamine signaling in BLA in controlling REM sleep, and at the same time, it also reveals the mechanism of cataplexy, which is expected to become a potential drug target for sleep disorders.
300 million people have sleep disorders
Spawned a 100-billion-level sleep aid market
According to the "China Sleep Research Report (2022)", the per capita sleep time in mainland China has decreased from 8.5 hours in 2012 to 7.06 hours in 2021 in the past 10 years, and the sleep duration has been significantly reduced, and the delay in falling asleep time has been serious. In addition, according to a survey by the China Sleep Research Association, the incidence of insomnia in Chinese adults is 38.2%, more than 300 million Chinese have sleep disorders, and difficulty falling asleep has become the most troublesome sleep problem for Chinese people, accounting for 54.6% [2]. The above data show that sleep disorders have become a major problem for Chinese people. Where there are challenges, there are natural opportunities, and more than 300 million Chinese people have sleep disorders, which is giving birth to a huge blue ocean market - sleep economy.
First, the Chinese people's awareness of sleep health has increased, and the demand for sleep assistance has grown rapidly
According to the "2022 Online Sleep Consumption Report" released by the Jingdong Consumer and Industrial Development Research Institute, the consumer demand for sleep assistance has grown rapidly: the turnover of online sleep aid products in 2021 increased by 53% year-on-year; the turnover of county-level rural sleep aid products increased by 149% year-on-year; and the transaction amount of intelligent sleep devices, sleep ventilators and smart beds for the 26-35 age group in 2021 increased by 208%, 167% and 106% respectively [3]. From the above data, it can be seen that national sleep sub-health is a universal social phenomenon, and at the same time, from the rapidly growing consumption of sleep aid products, it can also be seen that the chinese people's sleep health awareness is gradually improving, which will help the rapid growth of sleep aid demand.
With the continuous improvement of sleep health awareness, more and more consumers are willing to pay for high-quality sleep, the sleep aid economic market is good, and various types of sleep aid products have come into being. The data shows that the most popular sleep aids for consumers include sleep aids, massagers and physiotherapists (Figure 3).
Figure 3 Top 10 transaction amount of various sleep aid products in 2021 (data source: reference [4] | tabulation: biological exploration editing team)
The continuous growth of sleep demand has led to the rise of market segments, sleep aids have gradually diversified, and the sales of sleep aids represented by melatonin have grown rapidly. According to the sales situation of Jingdong, the turnover of sleep-assisting health care products in 2021 increased by 2.1 times year-on-year [3]. Eating melatonin, lighting scented candles, wearing steam eye masks, and plugging in anti-noise earplugs have become the "bedtime quadrilogy" of many people who have not slept well.
Second, the sleep economy market is vast, and the future of pharmaceutical and health care products can be expected
Nowadays, the pace of social life is fast and stressful, which will inevitably bring about increasingly serious sleep problems, and at the same time, the ravages of the new crown virus have made social emotions relatively tense, and in this environment, sleep problems are even more prominent. Therefore, sleep problems will occupy a more prominent position in the health management of modern life, and the gradual modernization of social life will also prompt Chinese people to pay more attention to sleep health. Long-term sleep is likely to induce other types of diseases, the need for timely drug treatment, so the potential of pharmaceutical health care products is worth looking forward to, sleep drugs and health care products related companies are expected to usher in market dividends.
Insomnia symptoms in some people are caused by other mental illnesses, at this time it can not only be treated as a sleep problem, and may even involve the drug demand for other mental illnesses, symptomatic treatment can effectively solve sleep problems. At present, the drugs that clinically treat insomnia mainly include benzodiazepine receptor agonists (BZRAs), melatonin receptor agonists, appetite hormone receptor antagonists and antidepressants with hypnotic effects. BZRAs are divided into benzodiazepines (BZDs) and non-benzodiazepines (non-BZDs), the sales of these two types of drugs continue to grow; melatonin receptor agonists are also favored by consumers, the use of more is agomelatine, its sales volume and sales have shown a rapid growth trend; antidepressants because of their sedative effect, so they also have a certain sleep aid effect, coupled with the current increasing number of depression groups, it also has great potential for development. Therefore, at present, sleep aids will be promising. In addition, the mainland sleep-assisting health care products market is in the initial stage of development, and the penetration rate is expected to increase rapidly.
Protect the healthy sleep of the Chinese people
Pharmaceutical companies R & D on the road
300 million People have sleep disorders, which has directly spawned a 100-billion-level market, and a number of pharmaceutical companies have entered the sleep economy, which is a big health track.
First, the original base Huayi: focus on the original research drugs in the field of nervous system
In February, the clinical trial application of a new drug HY010101 for CNS with sleep-wake disorder was approved by NMPA. HY010101 is a sleep-regulating and rhythm-regulating drug for non-24-hour sleep-wake disorders that was approved for clinical trials. This small molecule drug is a candidate new drug project of Peking University and is an hpER2 phosphorylation kinase inhibitor.
Figure 4 Announcement results (Source: CDE)
Yuanji Huayi is a new drug incubation and development platform focusing on supporting the whole process of original research drugs in the field of nervous system, from laboratory research and development, preclinical research, clinical process design to clinical trial stage. Chemical drugs are one of the original Huayi R&D pipelines, which include rhythm-regulating drugs and sleep-regulating drugs, rhythm-regulating drugs to meet the huge demand for regulating jet lag, and sleep-regulating drugs to meet the huge demand for high-quality sleep and wakefulness. According to the news on its official website, Yuanji Huayi has innovatively established a new drug research and development system for the detection of sleep in an in vitro system to find sleep-regulating drugs.
Second, Bloomage Biology: Actively open up the field of functional foods such as sleep aids
Bloomage Bio is actively involved in the field of sleep-assisting foods, actively promoting the application of bioactive substances such as GABA in the food field, and has carried out research and development work on this, and GABA's research on the improvement of anxiety and insomnia is currently in the small trial stage.
GABA, the full name of γ-aminobutyric acid, is a non-protein amino acid present in the human body itself, which plays a vital role in human neuromodulation and is a sleep aid for high-stress groups. Long-term excited neuronal cells are difficult to relax, and GABA can play a regulatory role in it, they are like a "brake" messenger, exogenous GABA into the cell, through binding to GABA a receptor, improve the permeability of the cell membrane to anions, so that extracellular anions (CL-) into the cell, so that neuronal cells from excitement to rest. Therefore, when the human body consumes GABA, it can relax neurons and brains to relieve stress and improve sleep.
Bloomage Bio took the lead in investing in the research on GABA, screening from kimchi to the excellent, stable and non-toxic and harmless natural strain - Lactobacillus hisi as a fermentation bacterium, opening the way for mass production of GABA by fermentation method. According to the study of Bloomage Biological Research Institute, GABA has been confirmed to significantly improve sleep effects, the company also conducted volunteer trials, test data show that the use of GABA can significantly prolong the time of deep sleep, shorten the time to fall asleep, so that the brain can get a full rest, thereby relieving anxiety and relieving fatigue. Bloomage Bio's functional food brand "Black Zero" has a "stress-relieving system" food for balancing emotions, and its slogan is "Midnight to Take You Sweet Flight", the main ingredient is GABA. At present, Bloomage Bio's sleep-assisted food business has just started, and the proportion of revenue is not high, but it is likely to create a new explosive growth point in the future.
Figure 5 A pressure-relieving food under the Black Zero brand (Source: Bloomage Bio's official website)
Emotional distress, life pressure, work pressure has become the main factor affecting the poor sleep of modern people, "a sheep, two sheep, three sheep..." Every night, the voice of these "late-night shepherds" will be heard over the city. Dreams are important, but it's also important to get a good night's sleep. May you dream during the day and dream at night.
Written by | Muzijiu
Typography | Muzijiu
End
Resources:
[1] Hasegawa E, Miyasaka A, Sakurai K, et al. Rapid eye movement sleep is initiated by basolateral amygdala dopamine signaling in mice. Science. 2022 Mar4;375(6584):994-1000. doi: 10.1126/science.abl6618. Epub 2022 Mar 3. PMID:35239361.
[2] 2022 Chinese National Healthy Sleep White Paper
[3] 2022 Online Sleep Consumption Report
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