The glymphatic system (or glymphatic clearance pathway) is a functional waste clearance pathway for the mammalian central nervous system (CNS). The lymphatic system is responsible for removing extracellular proteins, excess fluid, and metabolic waste products from peripheral tissues. 1
Glymphatic flow answers the long standing question of how the sensitive neural tissue of the CNS functions in the absence of a conventional lymphatic circulation. The pathway consists of a para-arterial influx route for cerebrospinal fluid (CSF) to enter the brain parenchyma, coupled to a clearance mechanism for the removal of interstitial fluid (ISF) and extracellular solutes from the interstitial compartments of the brain and spinal cord. Exchange of solutes between the CSF and the ISF is driven by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space.
Clearance of soluble proteins, waste products, and excess extracellular fluid is accomplished through convective bulk flow of the ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels. 2
Figure 1 Mammalian Gymphatic System
A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state. Using a combination of diffusion ionophoresis techniques pioneered by Nicholson and colleagues, in vivo 2-photon imaging, and electroencephalography to confirm the wake and sleep states, Xia and Nedergaard demonstrated that the changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes such as amyloid beta. 3 4
Assuring proper sleep quality is critical to the glymphatic system. If sleep quality is compromised, then the glymphatic system will not function effectively to detoxify the brain during sleep.
A double-blind, placebo-controlled clinical trial, was conducted in Pavia, Italy and the results of the study were published in the Journal of the American Geriatric Society in January 2011. The title of the study is “The effect of melatonin, magnesium, and zinc on primary insomnia in long-term care facility residents in Italy: a double-blind, placebo-controlled clinical trial.” 5
The objective of the clinical trial was to determine whether nightly administration of melatonin, magnesium, and zinc improves primary insomnia in long-term care facility residents.
The clinical trial consisted of forty-three participants with primary insomnia (22 in the supplemented group, 21 in the placebo group) aged 78.3 ± 3.9. The participants took a food supplement:
- 5 mg melatonin
- 225 mg magnesium
- 11.25 mg zinc
mixed with 100 g of pear pulp) or placebo (100 g pear pulp) every day for 8 weeks, 1 hour before bedtime.
The food supplement resulted in considerably better overall PSQI scores than placebo (difference between groups in change from baseline PSQI score=6.8; 95% confidence interval=5.4-8.3, P<.001). Moreover, the significant improvements in all four domains of the LSEQ (ease of getting to sleep, P<.001; quality of sleep, P<.001; hangover on awakening from sleep, P=.005; alertness and behavioral integrity the following morning, P=.001), in SDQ score (P<.001), in total sleep time (P<.001), and in SF-36 physical score (P=.006) suggest that treatment had a beneficial effect on the restorative value of sleep.
The researchers concluded that the administration of nightly melatonin, magnesium, and zinc appears to improve the quality of sleep and the quality of life in long-term care facility residents with primary insomnia.
Video: Scientists Discover Previously Unknown Cleaning System in Brain Newer Imaging Technique Brings ‘Glymphatic System’ to Light (Jeffrey Iliff, University of Rochester Medical Center)
Video: National Institutes of Health – Brain Opens Up The Pipes During Sleep
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