Melatonin in ventricular and subarachnoid cerebrospinal fluid: Its function in the neural glymphatic network and biological significance for neurocognitive health

Reíter, Russel J.; Sharma, Ramaswamy; Rosales-Corral, Sergio; Mange, Jasmine De; Phillips, William T.; Tan, Dun Xian; Bitar, Ryan

doi:10.1016/j.bbrc.2022.03.025

Cited by 22 publications

(19 citation statements)

References 162 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Melatonin is both water- and lipid-soluble (‘amphiphilic’); thereby, it can freely flow among all bodily tissues, especially across the selective blood–brain barrier, making it likely one of the most formidable antioxidants within the central nervous system [ 60 ]. 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 ]. Theoretically, based on this finding, it may be worthwhile from a therapeutic perspective to dose melatonin so that older adults with neurodegenerative conditions could increase cerebrospinal and glymphatic fluid levels.…”

Section: Clinical Usesmentioning

confidence: 99%

Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements

Minich

Henning²,

Darley

et al. 2022

Nutrients

View full text Add to dashboard Cite

Melatonin has become a popular dietary supplement, most known as a chronobiotic, and for establishing healthy sleep. Research over the last decade into cancer, Alzheimer’s disease, multiple sclerosis, fertility, PCOS, and many other conditions, combined with the COVID-19 pandemic, has led to greater awareness of melatonin because of its ability to act as a potent antioxidant, immune-active agent, and mitochondrial regulator. There are distinct similarities between melatonin and vitamin D in the depth and breadth of their impact on health. Both act as hormones, affect multiple systems through their immune-modulating, anti-inflammatory functions, are found in the skin, and are responsive to sunlight and darkness. In fact, there may be similarities between the widespread concern about vitamin D deficiency as a “sunlight deficiency” and reduced melatonin secretion as a result of “darkness deficiency” from overexposure to artificial blue light. The trend toward greater use of melatonin supplements has resulted in concern about its safety, especially higher doses, long-term use, and application in certain populations (e.g., children). This review aims to evaluate the recent data on melatonin’s mechanisms, its clinical uses beyond sleep, safety concerns, and a thorough summary of therapeutic considerations concerning dietary supplementation, including the different formats available (animal, synthetic, and phytomelatonin), dosing, timing, contraindications, and nutrient combinations.

show abstract

Section: Clinical Usesmentioning

confidence: 99%

Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements

Minich

Henning²,

Darley

et al. 2022

Nutrients

View full text Add to dashboard Cite

show abstract

“…In our study, we found that cluster formation is elicited by KET at 100 nM, which is a concentration 2–3 orders of magnitude lower than anesthetic and psychomimetic doses. Similarly, we found MEL effects on neurogenesis at 100 nM, which is the concentration present in the cerebrospinal fluid at night [ 42 ]. Therefore, because the KET/MEL combination induces its neurogenic effects at nanomolar concentrations, which does not cause psychomimetic effects, it could be useful as a rescue therapeutic pharmacological treatment to those patients with depression resistant to treatment or those with suicidal ideations, because the antidepressant effects may be obtained in a therapeutically safe window, quickly and without collateral undesirable effects.…”

Section: Discussionmentioning

confidence: 88%

Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors

et al. 2022

View full text Add to dashboard Cite

Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.

show abstract

“…Melatonin treatment of AD transgenic mice increases Aβ glymphatic clearance [ 78 , 79 ]. Relevant to this, melatonin is known to preserve slow-wave sleep in patients [ 80 ], a phase in which the glymphatic elimination of Aβ peptides increases considerably [ 81 ].…”

Section: Mechanism Of Action Of Melatonin Relevant To Long Covid Trea...mentioning

confidence: 99%

Possible Application of Melatonin in Long COVID

2022

View full text Add to dashboard Cite

Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, “long COVID”. Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially memory loss or “brain fog”), chronic fatigue, myalgia, and muscular weakness resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are of importance. Melatonin may be particularly effective at reducing the signs and symptoms of SARS-CoV-2 infection due to its functions as an antioxidant, anti-inflammatory, and immuno-modulatory agent. Melatonin is also a chronobiotic medication effective in treating delirium and restoring the circadian imbalance seen in COVID patients in the intensive care unit. Additionally, as a cytoprotector, melatonin aids in the prevention of several COVID-19 comorbidities, including diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases. This narrative review discusses the application of melatonin as a neuroprotective agent to control cognitive deterioration (“brain fog”) and pain in the ME/CFS syndrome-like documented in long COVID. Further studies on the therapeutic use of melatonin in the neurological sequelae of SARS-CoV-2 infection are warranted.

show abstract

Melatonin in ventricular and subarachnoid cerebrospinal fluid: Its function in the neural glymphatic network and biological significance for neurocognitive health

Cited by 22 publications

References 162 publications

Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements

Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements

Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors

Possible Application of Melatonin in Long COVID

Contact Info

Product

Resources

About