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Glymphatic System

 

Overview

It wasn’t until 2012 that the brain’s fluid-transport system, called the glymphatic system, was identified (1,2). This system has been described as one of the body’s basic housekeeping tasks, “sweeping away” excess fluid and metabolic waste, such as lactate, amyloid-beta and tau protein, while also regulating tissue immunity (2). It is the brain’s lymphatic system and serves as an interface between the brain and the body. There is a direct connection to the immune system, and it allows for communication between the brain and the circulatory, digestive, and lymphatic systems by secreting signaling molecules to the cerebrospinal fluid (2).

 

The glymphatic system is comprised of 3 main compartments (1,3):

  1. The glymphatic influx (bringing nutrients and oxygen to the brain)

  2. The exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF)

  3. The glymphatic efflux (draining cellular debris and waste from the brain)

 

As shown in Figure 1, like the brain, the eye also has a glymphatic system, which will not be specifically addressed in this article.

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Figure 1: The glymphatic system and Ocular Glymphatic System

Image Credit: Mogensen FLH, Delle C, Nedergaard M. The Glymphatic System (En)during Inflammation. Int J Mol Sci. 2021 Jul 13;22(14):7491. https://creativecommons.org/license/by/4.0/.

The strongest evidence of glymphatic activity is a result of sleep studies. The glymphatic system is highly active during sleep, notably during non-rapid eye movement (NREM) sleep, and it is largely inactive during wake periods (2). Research conducted at the University of Rochester found that during sleep and while under anesthesia there is a 60% increase in the interstitial space, allowing for an increased exchange of the CSF and ISF and improved clearance of metabolic wastes and toxins from the brain (4).

 

Factors that reduce glymphatic function (2):

  1. Chronic stress

  2. Circadian rhythm disorders

  3. Impaired sleep, lack of adequate sleep, insomnia

  4. Increasing age

Additionally, neuroinflammation impairs the glymphatic system from functioning properly and can further exacerbate the inflammatory process in the body by suppressing the clearance of inflammatory cytokines from the brain. Neuroinflammation results from traumatic brain injury (TBI), bacterial and viral infections, neurodegenerative diseases such as Alzheimer’s disease, and autoimmune diseases, such as Multiple Sclerosis. However, neuroinflammation can also occur as a result of peripheral inflammation (any activation of the innate or adaptive immune system) (1). 

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It is proposed that targeting the glymphatic system could be a potential treatment option for neuroinflammatory diseases and assist in “detoxifying the brain” (1).

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Melatonin – A Potential Therapy for the Glymphatic System

Melatonin, due to its anti-inflammatory properties, antioxidant effects, and impact on sleep, has demonstrated benefits for several neurodegenerative/neuroinflammatory diseases (5,6). Of note, melatonin is directly secreted from the pineal gland to the bloodstream for its actions as a hormone, however, melatonin is also found in the CSF, where it functions as a powerful antioxidant and anti-inflammatory agent (7). In research comparing phytomelatonin to synthetic melatonin, phytomelatonin was shown to be between 470%-957% more effective as an antioxidant and 646% more effective in its anti-inflammatory effect (8,9).

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Further, pineal-derived melatonin is at its highest at approximately 2 am, which is also when glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (R-GSSG) also are at their peak. “The highest activity of these enzymes and the highest concentration of GSH at night are most likely related to the intensification of processes leading to the removal of free radicals during sleep, which in turn leads to the inhibition of oxidative stress in the organism.” (10)

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Images Credit: Budkowska M, Cecerska-Heryć E, Marcinowska Z, Siennicka A, Dołęgowska B. The Influence of Circadian Rhythm on the Activity of Oxidative Stress Enzymes. Int J Mol Sci. 2022 Nov 17;23(22):14275. doi: 10.3390/ijms232214275. https://creativecommons.org/license/by/4.0/.

The glymphatic system clears metabolic waste, including amyloid-beta. When the production and clearance of amyloid-beta is imbalanced, this results in neurotoxicity, oxidative stress, neuroinflammation, and apoptosis. All, of which, are factors in the development of Alzheimer’s disease (AD) (3). Melatonin has been shown to decrease amyloid-beta production, assembly, and neurotoxicity, while also increasing the clearance of amyloid-beta through the glymphatic system (3).

AB clearance.jpg

Figure 2: The action of melatonin on amyloid-beta

Image credit: Li Y, Zhang J, Wan J, Liu A, Sun J. Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer’s disease. Biomedicine & Pharmacotherapy. 2020 Dec;132:110887.  https://creativecommons.org/license/by/4.0/.   

After being treated with melatonin, one animal study showed a 30-55% reduction in amyloid antibodies (Ab1-40 and Ab1-42) in the brain, with plasma Ab levels remaining unchanged, suggesting an improved clearance from the brain through the glymphatic/lymphatic system (3). It is also speculated that Ab clearance is more efficient as a result of melatonin’s impact on reducing cholesterol and Apo-E levels in the brain (3). While human studies have explored the successful use of melatonin for AD patients on sleep parameters and cognition, the measurement of Ab clearance remains an area for future research to be conducted.

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In Parkinson’s Disease (PD), the expression of the water channel (aquaporin 4) in the glymphatic system is “severely altered” and may explain the association of sleep loss in those with PD (11,12). Further, rapid eye movement sleep behavior disorder is an early sign of PD (12). One animal study found improved glymphatic clearance after the administration of melatonin (13). Multiple human studies have shown melatonin to be impactful at improving sleep, lowering inflammation (COX-2), and increasing antioxidant capacity in those with PD in doses ranging from 2 mg to 25 mg, with an average dose of 3 mg per day (11). Melatonin’s role as an antioxidant, chronobiotic, mitochondrial regulator, and improving glymphatic flow are mechanisms that “can stop the progression of PD” (11).  

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Melatonin-Supporting Neurogenesis

Neurotrophic factors (NTFs), such as brain-derived neurotrophic factor (BDNF), play a critical role in neurogenesis. Extrapineal melatonin has been likened to NTFs in its behavior as it participates in neuroplasticity and neurodevelopment (6). For example, melatonin has been shown to: (6)

  • increase the formation of new neurons by almost 70% and increase cell survival.

  • stimulate dendritogenesis, dendrite spine formation, dendritic arborization, and synaptogenesis.

  • simulate axogenesis.

  • provide neuroprotection in diseases whose treatment causes toxicity.

 

An animal study demonstrated that melatonin was a “potent activator of microglial anti-inflammatory signaling”, as observed in the increase of BDNF (5). Another study examined the use of 3 mg of melatonin nightly for 3 months in 35 obese children who had circadian rhythm sleep-wake disorder. In addition to measuring sleep quality and melatonin levels, serum BDNF was also measured. A significant increase in BDNF was observed (p=0.26) representing a strong correlation with melatonin concentrations, indicating that BDNF is a key regulator for circadian rhythm sleep-wake disorders (14).

 

Additional Lifestyle Strategies to Optimize Clearance of Toxins

  1. Omega- 3 fatty acid supplementation may improve glymphatic clearance and reduce amyloid-beta buildup (15).

  2. Intermittent fasting: Fasting one day and eating ad-lib the next day may help reduce amyloid-beta deposition (15).

  3. Reduce/Eliminate alcohol use: Intermediate and heavy alcohol use reduces glymphatic transport (15).

  4. Physical activity may accelerate glymphatic clearance (15).

  5. Stress Management to help reduce cortisol and subsequent amyloid buildup (15).

  6. Body posture may be part of the process

    • ​Lateral position preferred over supine (16)

    • Right lateral position is the most preferred (15)

 

Conclusion

Evidence provides support for the therapeutic use of melatonin for neurodegenerative diseases, healthy aging, oxidative stress and inflammation, and the regulation of circadian rhythm.

 

Research into our understanding of the glymphatic system and potential therapies to support it remains in its infancy stage. However, due to melatonin’s critical role as a hormone for regulating sleep (the time in which the glymphatic system is highly active), along with its anti-inflammatory properties, antioxidant effects, and ability to regulate the mitochondria, we can anticipate future research to include melatonin as a plausible therapy option for the glymphatic system. 

 

Written by Kim Ross, DCN

Reviewed by Deanna Minich, PhD

Last Updated May 22, 2023

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References

1. Mogensen FLH, Delle C, Nedergaard M. The Glymphatic System (En)during Inflammation. Int J Mol Sci. 2021 Jul 13;22(14):7491.

2. Hablitz LM, Nedergaard M. The glymphatic system: A novel component of fundamental neurobiology. Vol. 41, Journal of Neuroscience. 2021.

3. Li Y, Zhang J, Wan J, Liu A, Sun J. Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: A potential therapeutic molecule for Alzheimer’s disease. Biomedicine & Pharmacotherapy. 2020 Dec;132:110887.

4. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. Sleep Drives Metabolite Clearance from the Adult Brain. Science (1979). 2013 Oct 18;342(6156):373–7.

5. Merlo S, Caruso GI, Korde DS, Khodorovska A, Humpel C, Sortino MA. Melatonin Activates Anti-Inflammatory Features in Microglia in a Multicellular Context: Evidence from Organotypic Brain Slices and HMC3 Cells. Biomolecules. 2023 Feb 16;13(2):373.

6. Miranda-Riestra A, Estrada-Reyes R, Torres-Sanchez ED, Carreño-García S, Ortiz GG, Benítez-King G. Melatonin: A Neurotrophic Factor? Molecules. 2022 Nov 10;27(22):7742.

7. Reiter RJ, Sharma R, Rosales-Corral S, de Mange J, Phillips WT, Tan DX, et al. Melatonin in ventricular and subarachnoid cerebrospinal fluid: Its function in the neural glymphatic network and biological significance for neurocognitive health. Biochem Biophys Res Commun. 2022 May;605:70–81.

8. Minich DM, Henning M, Darley C, Fahoum M, Schuler CB, Frame J. Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients [Internet]. 2022;14(19). Available from: https://www.mdpi.com/2072-6643/14/19/3934/htm

9. Kukula-Koch W, Szwajgier D, Gaweł-Bęben K, Strzępek-Gomółka M, Głowniak K, Meissner HO. Is phytomelatonin complex better than synthetic melatonin? The assessment of the antiradical and anti-inflammatory properties. Molecules. 2021;

10. Budkowska M, Cecerska-Heryć E, Marcinowska Z, Siennicka A, Dołęgowska B. The Influence of Circadian Rhythm on the Activity of Oxidative Stress Enzymes. Int J Mol Sci. 2022;23(22).

11. Pérez-Lloret S, Cardinali DP. Melatonin as a Chronobiotic and Cytoprotective Agent in Parkinson’s Disease. Vol. 12, Frontiers in Pharmacology. 2021.

12. Cardinali DP. Melatonin: Clinical perspectives in neurodegeneration. Vol. 10, Frontiers in Endocrinology. 2019.

13. Pappolla MA, Matsubara E, Vidal R, Pacheco-Quinto J, Poeggeler B, Zagorski M, et al. Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis. Curr Alzheimer Res. 2018;15(7).

14. Huang X, Huang Y, Hu B. Melatonin Treatment of Circadian Rhythm Sleep-Wake Disorder in Obese Children Affects the Brain-Derived Neurotrophic Factor Level. Neuropediatrics. 2023 Jan 12;

15. Reddy OC, van der Werf YD. The Sleeping Brain: Harnessing the Power of the Glymphatic System through Lifestyle Choices. Brain Sci. 2020 Nov 17;10(11):868.

16. Lee H, Xie L, Yu M, Kang H, Feng T, Deane R, et al. The Effect of Body Posture on Brain Glymphatic Transport. Journal of Neuroscience. 2015 Aug 5;35(31):11034–44.

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