Neural glymphatic system: Clinical implications and potential importance of melatonin

The central nervous system was thought to lack a lymphatic drainage until the recent discovery of the neural glymphatic system. This highly specialized waste disposal network includes classical lymphatic vessels in the dura that absorb fluid and metabolic by-products and debris from the underlying cerebrospinal fluid (CSF) in the subarachnoid space. The subarachnoid space is continuous with the Virchow-Robin peri-arterial and peri-vascular spaces which surround the arteries and veins that penetrate into the neural tissue, respectively. The dural lymphatic vessels exit the cranial vault via an anterior and a posterior route and eventually drain into the deep cervical lymph nodes. Aided by the presence of aquaporin 4 on the perivascular endfeet of astrocytes, nutrients and other molecules enter the brain from peri-arterial spaces and form interstitial fluid (ISF) that baths neurons and glia before being released into peri-venous spaces. Melatonin, a pineal-derived secretory product which is in much higher concentration in the CSF than in the blood, is believed to follow this route and to clear waste products such as amyloid-β from the interstitial space. The clearance of amyloid-β reportedly occurs especially during slow wave sleep which happens concurrently with highest CSF levels of melatonin. Experimentally, exogenously-administered melatonin defers amyloid-β buildup in the brain of animals and causes its accumulation in the cervical lymph nodes. Clinically, with increased age CSF melatonin levels decrease markedly, co-incident with neurodegeneration and dementia. Collectively, these findings suggest a potential association between the loss of melatonin, decreased glymphatic drainage and neurocognitive decline in the elderly.

Melatonin reduces the mortality of severely-infected COVID-19 patients

SARS-CoV-2 has ravaged the population of the world for two years. Scientists have not yet identified an effective therapy to reduce the mortality of severe COVID-19 patients. In a single-center, open-label, randomized clinical trial, it was observed that melatonin treatment lowered the mortality rate by 93% in severely-infected COVID-19 patients compared with the control group (see below). This is seemingly the first report to show such a huge mortality reduction in severe COVID-19 infected individuals with a simple treatment. If this observation is confirmed by more rigorous clinical trials, melatonin could become an important weapon to combat this pandemic.

Strategies to generate melatonin-enriched transgenic rice to respond to the adverse effects on rice production potentially caused by global warming

Global warming is predicted to reduce the yield of rice, which feeds more than half of the world’s population. A rise in temperature will inevitably hamper rice production by causing drought and flooding. Melatonin has the capacity to ameliorate such adverse effects. Here, we propose multiple genetic means of producing melatonin-enriched, high-yield rice variants to adapt upcoming global warming.

Melatonin, tunneling nanotubes and anastasis: Cheating cell death

When healthy neurons are exposed to toxins or physiological insults such as ischemia, apoptosis is often initiated. Once underway, this mechanistically-well described process was thought to routinely run its course with the disintegration of the cell and phagocytosis of the debris. Within the last decade, the consistency of this process has been questioned. It is now known that some damaged cells can recover, i.e., they avoid death; this restoration process is referred to as anastasis. The reestablishment of a healthy cell phenotype is highly energy-requiring, so optimally functioning mitochondria are obviously beneficial during the regenerative process. Some healthy mitochondria that end up in regenerating cells are transferred there by adjacent healthier cells through tunneling nanotubes. Tunneling nanotubes generally form under stressful conditions when these micron-size tubules link adjacent cells. These tubules transfer soluble factors and organelles, including mitochondria, between the connected cells. When damaged cells receive high APT-producing mitochondria via this means, they support the ability of the cells to recover. Two recent comprehensive publications show that melatonin aids the transfer of mitochondria through nanotubes that connect neurons thereby likely assisting the recovery of the damaged recipient cell. Thus, melatonin not only protects normal neurons from damage by neutralizing the agents that initiate apoptosis, e.g., free radicals, etc., but also reverses this process once it is underway.

Melatonin and calpeptin synergistically protect against post-reperfusion injury in a rat middle cerebral artery occlusion stroke model

Cerebral ischemia induces oxidative injury and increases the intracellular calcium ion concentration to activate several calcium-dependent proteases such as calpains. Calpain activation leads to various necrotic and apoptotic processes. Calpeptin is a potent, cell-permeable calpain inhibitor. As a strong antioxidant and free radical scavenger, melatonin shows beneficial effect in rodent models of focal cerebral ischemia when given prior to ischemia or reperfusion. This study was focused on the neuroprotective effects of melatonin and/or calpeptin given after onset of reperfusion. For this purpose, right-sided middle cerebral artery occlusion (MCAO) for 90 minutes followed by 24 or 72 hours of reperfusion was performed in male Sprague Dawley rats, then, melatonin 50 or 150 µg/kg, calpeptin 10, 15 or 50 µg/kg or a combination of melatonin 50 µg/kg plus calpeptin 15 or 50 µg/kg were injected via an intracerebroventricular route at 15 minutes after onset of reperfusion. Melatonin or calpeptin tended to reduce the relative infarct volume and significantly decreased the neurological deficit at 24 hours. The combination achieved a greater protection than each of them alone. Melatonin, calpeptin or the combination all decreased Fluoro-Jade B (FJB)+ degenerative neurons and cleaved/total caspase-3 ratio at 24 hours. These treatments did not significantly impact the density of surviving neurons and ED-1+ macrophage/activated microglia. At the 72-hour-reperfusion, melatonin or the combination decreased the relative infarct volume and neurological deficit. Nevertheless, only the combination reduced FJB+ degenerating neurons at 72 hours. In conclusion, a combination of melatonin and calpeptin exerted synergistic protection against post-reperfusion injury in a rat MCAO stroke model.

Functional characterization of tobacco (Nicotiana benthamiana) serotonin N-acetyltransferases (NbSNAT1 and NbSNAT2)

Nicotiana benthamiana (tobacco) is an important dicotyledonous model plant; however, no serotonin N-acetyltransferases (SNATs) have been characterized in tobacco. In this study, we identified, cloned, and characterized the enzyme kinetics of two SNAT genes from N. benthamiana, NbSNAT1 and NbSNAT2. The substrate affinity (Km) and maximum reaction rate (Vmax) for NbSNAT1 were 579 µM and 136 pkat/mg protein for serotonin, and 945 µM and 298 pkat/mg protein for 5-methoxytryptamine, respectively. Similarly, the Km and Vmax values for NbSNAT2 were 326 µM and 26 pkat/mg protein for serotonin, and 872 µM and 92 pkat/mg protein for 5-methoxytryptamine, respectively. Moreover, we found that NbSNAT1 and NbSNAT2 localized to chloroplasts, similar to SNAT proteins from other plant species. The activities of the NbSNAT proteins were not affected by melatonin feedback inhibition in vitro. Finally, transgenic tobacco plants overexpressing either NbSNAT1 or NbSNAT2 did not exhibit increased melatonin levels, possibly due to the expression of catabolic enzymes. Generating transgenic tobacco plants with downregulated NbSNAT expression would provide further insight into the functional role of melatonin in tobacco plants.

Oral administration of melatonin increases plasma calcium and magnesium and improves bone metabolism in aged male mice

We previously reported that the oral administration of melatonin from 4 to 20 months to male mice improved femoral bone strength and bone density during the aging. Additionally, melatonin receptor, MT2, was immunologically detected in both osteoblasts and osteoclasts of the mouse femoral bone. Thus, melatonin can act on both osteoblasts and osteoclasts to maintain bone strength during the aging process. Here, we analyzed plasma calcium (Ca2+), magnesium (Mg2+), and inorganic phosphorus ([PO4]3-) in 20-month-old male mice with or without administration melatonin (15-20 mg/kg/day) in drinking water. We found that plasma Ca2+ and Mg2+ levels in melatonin-treated mice increased significantly as compared with control mice. In [PO4]3-, melatonin administration tended to increase its plasma level, but did not reach statistical significance. The potential association between these divalent ions and metabolism markers of femoral bone was also examined. In the femoral diaphysis, the plasma Ca2+ and Mg2+ concentrations were positively correlated with periosteal and endosteal circumference which were significantly associated with the Strength Strain Index. Therefore, melatonin treatment enlarged femoral diaphysis and enhanced bone strength by increasing mineral depositions. In addition, the plasma melatonin levels were significantly positive correlation with total bone density and critical thickness in the femoral diaphysis. Since we had not observed the primary trabecular bone and osteoclasts in 20-month-old mice previously, it is suggested that plasma Ca2+ and Mg2+ are not elevated due to bone resorption. The increased plasma Ca2+ and Mg2+ by melatonin may originate from the intestinal absorption of these ions since melatonin binds to the vitamin D3 receptor, its activation is known to promote the intestinal absorption of Ca2+.

Potentially synergistic effects of melatonin and metformin in alleviating hyperglycaemia: a comprehensive review

High level of glucose is hazardous for organisms since it leads to lipid peroxidation, protein glycation and free radical generation. Insulin can lower the high blood glucose by promoting cell’s glucose up-taking. Thus, the impeded insulin secretion in type 1-diabetes and insensitivity of cells to insulin in type 2-diabetes cause hyperglycaemia. Hyperglycaemia impairs mitochondrial function of pancreas to trigger ROS generation. The malfunctional mitochondria cause endoplasmic reticulum to produce misfolded non-functional insulin, finally leading to diabetes. Melatonin, the mitochondria targeted antioxidant, provides protection against diabetes by multiple ways. These include balancing cellular redox status, lowering blood glucose level by modulating metabolic pathways and, finally protecting cells/organelles from high glucose induced injury. Moreover, this indoleamine preserves pancreatic physiological normalcy to facilitate insulin secretion. Thus, melatonin can effectively mitigate diabetes and diabetic complications. Metformin, the most prescribed medicine for type 2-diabetes, has similar antidiabetic activities as melatonin. Both the molecules share similar pathways to preserve stress-stricken pancreas and other organs, whereas, melatonin also potentiates the actions of metformin. The potentially synergistic actions of melatonin and metformin are expected and we strongly recommend a combined therapeutic application of these two molecules for treatment of diabetes.

Melatonin: an ancient note in a contemporary wrap

At the beginning of life, natural selection is and still the principal driving force for the evolution of all organisms to adapt in the particular environments of the earth. As a result, ultimately neither the strongest, nor the supreme intelligent but the most adaptable species win the race. Not only the organisms, but also the elements which are necessary for survival of them also undergo extreme evolution. These include DNA, proteins and other biochemical moleculesAt the beginning of life, natural selection is and still the principal driving force for the evolution of all organisms to adapt in the particular environments of the earth. As a result, ultimately neither the strongest, nor the supreme intelligent but the most adaptable species win the race. Not only the organisms, but also the elements which are necessary for survival of them also undergo extreme evolution. These include DNA, proteins and other biochemical molecules. However, melatonin, an indoleamine, presents in the early life form remains unchanged in its structure from unicellular organisms to mammals. When it was discovered, it was considered to be a neuronal hormone produced exclusively in the pineal gland of vertebrates. The latter discovery of its presence in primitive bacteria drives the melatonin research in different directions. Its primary function is serving as an antioxidant in all organisms. Its chemical structure is perfect to scavenge free radicals and thus, this molecule is preserved from bacteria to mammals. However, this molecule acquired many additional functions during evolution. These include circadian regulation, immuno-enhancement, oncostatic, anti-inflammatory and anti-aging activities. In the review, we are trying to present hypothetical and most plausible chronological events in the functional evolvements of melatonin during the process of evolution.

Could melatonin be an adjunct therapy for post-TB lung disease?

Post-tuberculosis (post-TB) lung disease is a complex interplay between organism, host, and environmental factors, and it affects long-term respiratory health. It associates with underlying processes such as inflammation, fibrosis, and oxidative stress. Decades of research has demonstrated melatonin as a potent anti-inflammatory, anti-fibrotic, antioxidant, and vasodilatory agent. These effects have been observed in numerous experimental and clinical models of lung diseases. Moreover, melatonin has significant anti-microbial activity, which has also been observed in the context of TB bacterial growth. It is worth pointing out that these effects of melatonin are a reminder of the pathologic processes that underpin post-TB lung disease. Based on the intriguing evidence presented and discussed in this paper, melatonin could be considered a safe, affordable, and adjunct therapy against post-TB lung disease. Melatonin may provide health benefits in this context, mediated via its anti-inflammatory, anti-fibrotic, vasodilatory, antimicrobial and antioxidant properties.