Melatonin in ventricular and subarachnoid cerebrospinal fluid: Its function in the neural glymphatic network and biological significance for neurocognitive health
Abstract
The central nervous system (CNS) is endowed with a specialized cerebrospinal fluid (CSF)/lymph network which removes toxic molecules and metabolic by-products from the neural parenchyma; collectively, this has been named the glymphatic system. It allows CSF located in the subarachnoid space which surrounds the CNS to enter the depths of the brain and spinal cord by means of Virchow-Robin perivascular and perivenous spaces. CSF in the periarterial spaces is transferred across the astrocytic end feet which line these spaces aided by AQ4 channels; in the interstitium, the fluid moves via convection through the parenchyma to be eventually discharged into the perivenous spaces. As it passes through the neural tissue, the interstitial fluid flushes metabolic by-products and extracellular toxins and debris into the CSF of the perivenous spaces. The fluid then moves to the surface of the CNS where the contaminants are absorbed into true lymphatic vessels in the dura mater from where it is shunted out of the cranial vault to the cervical lymph nodes. Pineal melatonin released directly into the CSF causes the concentration of this molecule to be much higher in the CSF of the third ventricle than in the blood. After the ventricular melatonin enters the subarachnoid and Virchow-Robin spaces it is taken into the neural tissue where it functions as a potent antioxidant and anti-inflammatory agent. Experimental evidence indicates that it removes pathogenic toxins, e.g., amyloid-β and others, from the brain to protect against neurocognitive decline. Melatonin levels drop markedly during aging, coincident with the development of several neurodegenerative diseases and the accumulation of the associated neurotoxins.
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Preliminary research indicates that melatonin may be an active component in the glymphatic fluid, assisting in removing metabolic waste such as amyloid buildup.
“Preliminary research also indicates that it may be an active component in the glymphatic fluid, assisting in removing metabolic waste such as amyloid buildup [61].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [61]
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Melatonin and its metabolites as chemical agents capable of directly repairing oxidized DNA
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Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders
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Evidence of High Concentrations of Melatonin in Lateral Ventricular Cerebrospinal Fluid of Sheep
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When the Brain Yearns for Oxygen
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The Formation, Metabolism, and Physiologic Effects of Melatonin†
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What Is the “Glymphatic System”?
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Minich, D. M., Henning, M., Darley, C., Fahoum, M., Schuler, C. B., & Frame, J. (2022) · Nutrients · doi:10.3390/nu14193934 · Cited by 176 · see citing works
“Preliminary research also indicates that it may be an active component in the glymphatic fluid, assisting in removing metabolic waste such as amyloid buildup [61].”
Background
- Authors
- Reiter, R. J., Sharma, R., Rosales-Corral, S., de Mange, J., Phillips, W. T., Tan, D. X., & Bitar, R. D.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Yale University (US)
- Corresponding author
- Reiter, Russel J.
- Sharma, Ramaswamy
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2022-05
- Volume
- 605
- Pages
- 70-81
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W4220845209
- Cited by
- 31
- References
- 168
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 8 · 2023: 11 · 2022: 6
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- melatonin, cerebrospinal fluid, glymphatic system, subarachnoid space, third ventricle, perivascular spaces, astrocytes, amyloid-beta clearance, neuroinflammation, antioxidant activity, neurodegenerative diseases, aging, neurocognitive decline, pineal gland
- MeSH terms
- Brain, Cerebrospinal Fluid, Melatonin
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