The glymphatic system is the recently discovered cleansing system of the brain. Similarly to the lymphatic system for the rest of the body, it allows the metabolic waste products to be taken out of the central nervous system.
The glymphatic system is known to be most active during sleep, but there are other factors determining its efficiency.
For example, the aquaporin AQP4, a protein facilitating the flow of water across membranes (and which is linked to the NFAT5/TonEBP transcription factor involved in the protection against hyperosmolarity/osmotic stress), is thought to be necessary for the proper flow of the fluids involved in this cleansing system. A model of its functioning is depicted in the figure below:
Principal features of the proposed glymphatic circulation. Periarterial inflow of cerebrospinal fluid, shown on the left, enters the interstitial fluid in the parenchyma by crossing a layer of glial endfeet assisted by the presence of aquaporin 4 (AQP4) water channels in the endfoot membrane facing the perivascular space. The fluid then flows through the interstitial spaces propelling solutes towards the perivenous conduits, shown on the right, leading to outflow from the brain.
The glymphatic hypothesis: the theory and the evidence
Melatonin could also be one of these factors. The following publication hypothesizes that melatonin could be fundamentally associated with the glymphatic system:
Melatonin induces sleep which is associated with a greatly increased clearance of toxic molecules from the glymphatic system. Maximum secretion of melatonin corresponds with the time when the glymphatic system is the most active suggesting that melatonin is integral to the process of waste removal and neuroprotection during sleep. Other evidence suggests that the glymphatic system is important for the movement of melatonin through the brain. […]
The glymphatic system would appear to be an important transport system for moving high concentrations of melatonin released directly into the CSF from the pineal gland into neurons and glia throughout the CNS. The movement of high concentrations of melatonin through the glymphatic system has important implications for a variety of neurodegenerative diseases such as AD, Parkinson disease, Huntington disease, etc., all of which have a free radical and/or inflammatory component.
Neural glymphatic system: Clinical implications and potential importance of melatonin
Vasopressin, the antidiuretic hormone which is produced when blood osmolarity increases (so that kidneys retain water), could be related to the glymphatic system via both melatonin and the aquaporin AQP4.
Indeed, the following publication found that vasopressin was probably increasing the flux of water in the cortex (in an in-vitro experiment) through AQP4.
Our data are consistent with the idea that vasopressin through V1a receptors facilitates an activity-dependent flux of water through the cortical astrocyte syncytium. The rapid time course of the volume changes suggests that the effect of vasopressin is mediated by modulation of a specialized water channel, most probably aquaporin-4.
Moreover, hyperosmolarity was found to boost the glymphatic flux in the brain (by acting upon NFAT5 and/or via vasopressin increase?):
We here utilized transcranial macroscopic imaging to noninvasively evaluate in vivo delivery pathways of CSF fluorescent tracers. [...] CSF tracer entry was enhanced approximately 3-fold by increasing plasma osmolality without disruption of the blood-brain barrier. Further, plasma hyperosmolality overrode the inhibition of glymphatic transport that characterizes the awake state and reversed glymphatic suppression in a mouse model of Alzheimer’s disease.
Finally, it seems like vasopressin can influence the secretion of melatonin (in rats):
Melatonin synthesis potentiation was achieved when vasopressin was infused locally in the pineal, during the onset of nocturnal melatonin secretion. In order to assess the possible role of a physiological increase of endogenous circulating vasopressin on pineal metabolism, melatonin synthesis was recorded in the same animals before and after a prolonged dehydration period. Night time melatonin concentration was increased after the water deprivation vs control conditions.
TLDR:
Brain's metabolic waste products are removed from the brain by the glymphatic system, which is most active during sleep.
This cleansing system could be boosted by vasopressin and/or hyperosmolarity.
Melatonin, which is involved in sleep/circadian rhythms and whose secretion seems to be increased by vasopressin or “dehydration”, could be importantly associated with the glymphatic system efficiency.