Inhibiting nighttime melatonin and boosting cortisol increase patrolling monocytes, phagocytosis, and myelination in a murine model of multiple sclerosis

Abstract

Conflicting results on melatonin synthesis in multiple sclerosis (MS) have been reported due to variabilities in patient lifestyles, which are not considered when supplementing melatonin. Since melatonin acts through its receptors, we identified melatonin receptors in oligodendrocytes (OLs) in the corpus callosum, where demyelination occurs; the subventricular zone, where neural stem/progenitor cells (NSPCs) are located; and the choroid plexus, which functions as a blood-cerebrospinal fluid barrier. Moreover, using chimeric mice, resident macrophages were found to express melatonin receptors, whereas bone marrow-derived macrophages lost this expression in the demyelinated brain. Next, we showed that cuprizone-fed mice, which is an MS model, tended to have increased melatonin levels. While we used different approaches to alter the circadian rhythm of melatonin and cortisol, only the constant light approach increased NSPC proliferation and differentiation to oligodendrocyte precursor cells (OPCs), OPCs maturation to OLs and recruitment to the site of demyelination, the number of patrolling monocytes, and phagocytosis. In contrast, constant darkness and exogenous melatonin exacerbated these events and amplified monocyte infiltration. Therefore, melatonin should not be considered a universal remedy, as is currently claimed. Our data emphasize the importance of monitoring melatonin/cortisol oscillations in each MS patient by considering diet and lifestyle to avoid melatonin overdose.

Melatonin and vitamin D, two sides of the same coin, better to land on its edge to improve multiple sclerosis

“…Furthermore, it has been proposed that monocyte chemoattractant protein-1 [MCP-1, also known as chemokine ligand 2 (CCL2)], plays a key role in MS pathogenesis, most likely by recruiting peripheral monocytes via the blood–brain barrier (BBB) and parenchyma ( 26 ). This idea was examined in our recent study, in which we discovered that keeping mice in constant darkness results in an increased melatonin production by the pineal gland which causes a dramatic rise in the number of infiltrating monocytes into the brain of a MS model ( 27 ). Furthermore, investigating the correlation between daytime saliva melatonin and inflammatory cytokines uncovered a positive correlation between increased melatonin levels and MCP-1/CCL2, a finding that highlighted the bidirectional interaction between melatonin and the immune system ( 28 ).…”

“…Surprisingly, keeping mice in constant light, to suppress the pineal melatonin synthesis, and treating with an antagonist of melatonin receptors, to suppress the function of melatonin, caused a rescue of all the abovementioned events and improved the severity of the disease. Besides, this was associated with suppression of nighttime melatonin, near physiological concentration, and boosting cortisol levels ( 42 ). Therefore, we suggest the suppression of melatonin for improvement of MS; however, we claim that keeping melatonin at physiological concentrations is vital for improving the disease.…”

Bioactive Compounds and Their Influence on Postnatal Neurogenesis

“…This suggests that these receptors play a role in melatonin's beneficial effects on hippocampal neurogenesis and behavior [103]. Additionally, melatonin receptors have been identified in various other brain regions, including oligodendrocytes in the corpus callosum, the SVZ where neural stem/progenitor cells (NSPCs) are found, and the choroid plexus, which acts as a barrier between the blood and cerebrospinal fluid [104]. In vivo studies have shown that one-month-long delivery of melatonin in drinking water (4 mg/kg/day) after 24 h stroke onset influences neuronal survival and stimulates neurogenesis in C57Bl6/j mice, leading to improvements in motor and coordination deficits (assessed using the RotaRod test) as well as behavioral adjustments (assessed in the open field test) [105].…”

“…Individualized approaches are essential to ensure safe and effective treatment. This emphasizes the importance of tailoring treatments to the specific needs and conditions of patients, especially when dealing with complex and multifaceted diseases like multiple sclerosis [104].…”

Changes in Melatonin Concentration in a Clinical Observation Study under the Influence of Low-Frequency Magnetic Fields (Magnetic Stimulation in Men with Low Back Pain)—Results of Changes in an Eight-Point Circadian Profile

“…The data emphasize the importance of monitoring diurnal changes in melatonin in every MS patient by considering diet and lifestyle to avoid overdosing on melatonin, which is not a panacea in all conditions. Previously, melatonin was thought to have universal positive regulating effects and that it could not be overdosed [17].…”