Some sleeping pills alter the brain’s cleaning system during sleep, which could affect long-term cognitive function and promote the onset of neurodegenerative diseases such as Alzheimer’s.
It is one of the warnings made by the authors of an investigation published this Wednesday in the magazine cell, in which the mechanism by which the brain eliminates waste while we sleep and gets rid of proteins whose accumulation can be harmful in the long term is described for the first time in great detail in mice.
It has long been known that sleep disorders, such as insomnia and apnea, can significantly affect health and sometimes precede the appearance of neurodegenerative diseases. In 2013, the Danish neuroscientist Maiken Nedergaard discovered the glymphatic systema network of channels in the brain whose purpose is to eliminate toxins by draining cerebrospinal fluid during sleep, including amyloid and tau proteins, associated with Alzheimer’s.
A decade later, and after the discovery of the complementary system of meningeal lymphatic vesselsNedergaard’s team has documented the process in great detail in mice thanks to the combination of a series of pioneering physiological monitoring techniques. And in the process they have encountered this unexpected effect of some sleeping pills.
Synchronized pumping
What Nedergaard and his team have documented are a series of closely synchronized oscillations of the neurotransmitter norepinephrine, cerebral blood, and cerebrospinal fluid that combine during non-REM sleep (non-rapid eye movement sleep). Using an optical technique called fiber flow photometry combined with electroencephalogram and electromyography monitors, the researchers were able to record the brain activity of the mice while they moved freely and during long uninterrupted periods of wakefulness and sleep.
The result draws attention to the potentially harmful effects on brain health of certain pharmacological sleep aids
Maiken Nedergaard
— Researcher at the University of Rochester and leader of the study
The research highlights the fundamental role of norepinephrine, a neurotransmitter associated with arousal, which triggered micro awakenings, causing rhythmic constriction of blood vessels independently of the heartbeat. This norepinephrine-induced oscillation, in turn, generates the pumping action necessary to move cerebrospinal fluid in the glymphatic system during sleep.
Interrupted cycles
Although the motivation for this research was to better understand what drives glymphatic flow during sleep, the authors also explored whether sleeping pills replicate the natural oscillations necessary for glymphatic function. The surprise came when verifying that the sleeping pill zolpidemcommonly prescribed for sleep problems under the brand name Ambien or Stilnox, suppresses these glymphatic system cycles, potentially setting the stage for neurological disorders like Alzheimer’s, which result from toxic buildup of proteins in the brain.
The authors found that norepinephrine waves during deep sleep were 50% lower in mice treated with zolpidem than in naturally sleeping mice. Although the mice treated with the sleeping pill fell asleep faster, fluid transport to the brain was reduced by more than 30%. These findings suggest, the researchers believe, that the sleeping pill may alter norepinephrine-driven waste elimination during sleep.
More and more people take sleep medications and it is very important to know if it is healthy sleep
Natalie Hauglund
— First author of the study and currently a postdoctoral researcher at the University of Oxford
“The result draws attention to the potentially harmful effects on brain health of certain pharmacological sleep aids, highlighting the need to preserve the natural architecture of sleep for optimal brain function,” underlines Nedergaard. “More and more people take sleep medications and it is very important to know if it is healthy sleep,” he says. Natalie Hauglundfirst author of the study and currently a postdoctoral researcher at the University of Oxford. “If people are not getting the full benefits of sleep, they need to know so they can make informed decisions.”
The team says the findings probably apply to humans, who also have a glymphatic system, although more testing is needed.
The team says the findings probably apply to humans, who also have a glymphatic system, although more testing is needed. Researchers have observed similar norepinephrine waves, blood flow patterns, and brain fluid flow in humans. Their findings may offer insight into how lack of sleep may contribute to neurological disorders such as Alzheimer’s disease.
The work is not the first to associate the consumption of sleeping pills with the risk of dementia. A study published in 2023 in the Journal of Alzheimer’s Disease, which involved about 3,000 older adults without dementia who were followed for 9 years, showed worrying results: those who took sleeping pills “often” or “almost always” were 79% more likely to develop dementia compared to those who “never” or “rarely” used them. Other recent work showed that zolpidem users with a high cumulative dose had a significantly higher risk of Alzheimer’s disease than users not taking it.
Cautious, but vigilant
“This excellent article explains how during the NREM sleep phase the entry of cerebrospinal fluid into the brain parenchyma is generated, which is a key element for the functioning of this system,” he says. Jordi Vilaplanaresearcher at the University of Barcelona (UB) and the Network Biomedical Research Center on Neurodegenerative Diseases (CYBERNED) to elDiario.es. “The article also shows that zolpidem suppresses glymphatic flow and thus makes it difficult to clean the brain parenchyma,” adds Vilaplana.
Although the work was carried out in mice, Vilaplana considers that the results are relevant, given that there are indications that the malfunction of the glymphatic system may be an important factor in some neurodegenerative diseases. In the expert’s opinion, it is necessary to be cautious in extrapolating results from animal models to humans, but the basic principles of the functioning of the glymphatic system seem to be common.
The results are relevant, given that there are indications that the malfunction of the glymphatic system may be an important factor in some neurodegenerative diseases.
Jordi Vilaplana
— Researcher at the University of Barcelona and CIBERNED
“In humans, as occurs in mice, the entry of fluid into the brain parenchyma also seems to occur mainly during sleep,” says Vilaplana. “From this perspective, any factor, whether pharmacological or not, that alters the sleep pattern is susceptible to altering the functioning of the glymphatic system.”
For the neuroscientist Amanda Sierraresearcher at the Achucarro Basque Center for Neuroscience, the study is a technical feat, because it is very difficult to measure all these parameters at the same time in an awake and moving mouse. “It seems to me that he has managed to demonstrate very convincingly this effect of these slow waves of norepinephrine on the elimination of cerebrospinal fluid, with the limitations that it has been done in mice, that it cannot be extrapolated to all drugs and that albumin The fluorescent light that they have measured in the cerebrospinal fluid is just a tracer, and the proteins that cause neurodegeneration, such as tau and amyloid, do not have to behave in exactly the same way,” he explains.
In any case, Sierra concludes, the result contributes to solving the mystery of how cerebrospinal fluid circulates during sleep phases to evacuate certain proteins, something that we have known for just over a decade. “The paradigm has changed and now we have come to consider sleep as an active mechanism of regeneration and cleansing,” he points out. “In that sense, no one thought that these drugs could have long-term effects, but their consumption for long periods could still be related to Alzheimer’s and this will have to be verified.”
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