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Melatonin and its precursors and metabolites may play a significant role in MS.
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Astrocyte as well as pineal derived melatonin is important to the course of MS.
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Melatonin and N-acetylserotonin modulate myelination and demyelination.
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Decreased melatonin links depression’s association with MS exacerbations.
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The modulation of local melatonin mediates many pharmaceutical effects in MS.
Abstract
Multiple sclerosis (MS) is an immune mediated disorder that is under intensive investigation in an attempt to improve on available treatments. Many of the changes occurring in MS, including increased mitochondrial dysfunction, pain reporting and depression may be partly mediated by increased indoleamine 2,3-dioxygenase, which drives tryptophan to the production of neuroregulatory tryptophan catabolites and away from serotonin, N-acetylserotonin and melatonin production. The consequences of decreased melatonin have classically been attributed to circadian changes following its release from the pineal gland. However, recent data shows that melatonin may be produced by all mitochondria containing cells to some degree, including astrocytes and immune cells, thereby providing another important MS treatment target. As well as being a powerful antioxidant, anti-inflammatory and antinociceptive, melatonin improves mitochondrial functioning, partly via increased oxidative phosphorylation. Melatonin also inhibits demyelination and increases remyelination, suggesting that its local regulation in white matter astrocytes by serotonin availability and apolipoprotein E4, among other potential factors, will be important in the etiology, course and treatment of MS. Here we review the role of local melatonin and its precursors, N-acetylserotonin and serotonin, in MS.
), with predominantly white matter, but also grey matter, loss. This is driven by increased T-helper (Th)17 and Th1 T cells, coupled to a decrease in regulatory T cells (RegT). Indoleamine 2,3-dioxygenase (IDO) activation in dendritic cells may increase RegT cell levels (
), whereas its activation in other cell types predominantly takes tryptophan down the tryptophan catabolite (TRYCAT) pathways and away from serotonin, N-aceylserotonin (NAS) and melatonin production (
The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression.
Measures of melatonin in MS have focused on pineal gland synthesis and efflux, spurred by data showing MS susceptibility genes in tryptophan hydroxylase-2 and melatonin receptors, which are associated with primary and secondary progressive MS (
). When given to secondary progressive MS patients melatonin decreases the oxidative stress in red blood cells, as indicated by decreased lipid peroxidation and increased endogenous antioxidants, superoxide dismutase and glutathione peroxide (
), which the authors suggest indicates a role of melatonin in modulating the effects of vitamin D. Previously we suggested efficacious interactions of vitamin D and melatonin with valproate in MS treatment, especially in the case of emergent seizures (
), rather than on pineal derived melatonin. Here we review recent data on the production of central melatonin and its relevance in MS. First we say something on melatonin.
2. Melatonin and MS
2.1 Melatoninergic pathway regulation
N-Acetyl-5-methoxytryptamine (melatonin) is a methoxyindole that is produced at night by the pineal gland. Pineal nighttime melatonin production is mediated by norepinephrine (NE), and is a powerful circadian regulator. Melatonin is a potent anti-oxidant, anti-inflammatory, immune regulator and inducer of endogenous anti-oxidants, as well as optimizing mitochondrial oxidative phosphorylation (
). Melatonin production is dependent on the availability of serotonin, which is converted by arylalkylamine N-acetylatransferase (AA-NAT) to N-acetylserotonin (NAS), which is further converted to melatonin by hydroxyindole O-methyltransferase (HIOMT) (also known as acetylserotonin O-methyltransferase). In melatonin producing cells both NAS and melatonin are readily effluxed and, being lipophilic, readily cross cell membranes; see Fig. 1.
Fig. 1Astrocyte release of NAS and melatonin will have significant impacts on neighbouring microglia, macrophages and oligodendrocytes. By decreasing microglia and macrophage reactivity and inducing a phagocytic phenotype, astrocyte derived melatonin will have anti-inflammatory effects, contributing to decreased BBB permeability. Either or both NAS and melatonin will increase BDNF, sirtuins, MeCP2 and possibly miR-7 in oligodendrocytes, decreasing the likelihood of demyelination, whilst also increasing oligodendrocyte progenitor maturation and remyelination. As well as the proven effects of serotonin availability and ApoE4 in the regulation of astrocyte NAS and melatonin efflux, other factors, known to regulate NAS and melatonin in other cell types, are likely to influence their efflux from astrocytes, including B2-adr, cAMP, 14-3-3, leptin, YY1 and other processes involved in reactivation. Medications are likely to act on such NAS/melatonin modulators to influence their efflux. Stress and peripheral inflammation, by increasing IDO and TDO will decrease serotonin availability; thereby decreasing NAS and melatonin efflux in conjunction with increased risk of depression, somatization, fatigue and TRYCAT induced cognitive deficits. Oligodendrocytes, microglia and macrophages will also produce melatonin to some degree, although not included for clarity. Acronyms are detailed in the main text.
The metabolites of melatonin, including N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), also have anti-inflammatory, anti-oxidant and immuno-regulatory effects (
). Melatonin readily passes through cell membranes often accumulating in intracellular organelles, especially mitochondria. However, many of its effects are driven by the activation of melatonin receptors (MT1r and MT2r). Decreased melatonin, melatoninergic pathway enzymes and melatonin receptor single nucleotide polymorphisms (SNP) are common to many disorders, including MS (
). A number of factors modulate NE induced pineal melatonin production, which is increased by 14-3-3, whilst being decreased by tumor necrosis factor-alpha (TNF-α) and substance P (SubP), as well as being variably regulated by leptin (
In vitro effects of 5-hydroxytryptophan, indoleamines and leptin on arylalkylamine N-acetyltransferase (AA-NAT) activity in pineal organ of the fish, Clarias gariepinus (Burchell, 1822) during different phases of the breeding cycle..
Increased homocysteine occurs in MS, especially in association with the fat mass and obesity-associated (FTO) SNP rs9939609, with homocysteine being decreased by folate supplementation (
The fat mass and obesity-associated FTO rs9939609 polymorphism is associated with elevated homocysteine levels in patients with multiple sclerosis screened for vascular risk factors.
). Increased homocysteine and decreased folate decrease S-adenosylmethionine, in turn depriving the methyl source that is necessary for melatonin formation from NAS. Increased homocysteine and decreased melatonin would then contribute to elevated risk of cardiovascular disorders in MS (
Overall, a number of factors can influence the regulation of melatonin synthesis, some of which are altered in MS. However, much of the work on melatonin has focused on its synthesis and release by the pineal gland. Recent work shows melatonin to be produced by many other cells.
2.2 Glia, immune cell and local melatonin synthesis
Many cells can produce melatonin and NAS, including macrophages (
NF-kB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene.
). The role for known regulators of pineal NAS and melatonin synthesis, such as NE, cyclic adenosine monophosphate (cAMP), 14-3-3, leptin and SubP awaits investigation. Given its powerful protective effects in cells, local astrocyte melatonin regulation is a significant treatment target for a range of central conditions, including MS (
). As such, NAS is also likely to have protective effects, although different to those of melatonin, suggesting that the melatonin/NAS ratio may be of some biological significance.
Recent conceptualizations of non-pinealocyte melatonin synthesis suggest that mitochondria, and therefore almost all eukaryotic cells, produce melatonin to some degree (
Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes.
Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes.
). Deficits in mitochondrial functioning are evident in many psychiatric and neurodegenerative conditions, including MS. In a viral MS model, we have previously shown mitochondrial dysfunction to correlate with axonal loss (
Quantitative ultrastructural analysis of a single spinal cord demyelinated lesion predicts total lesion load, axonal loss, and neurological dysfunction in a murine model of multiple sclerosis.
), highlighting the importance of mitochondrial dysfunction. As such, melatonin and NAS synthesis may be intimately associated with mitochondrial function across a range of cell types.
2.3 Astrocytes, melatonin and inflammation in MS
Although grey matter losses are evident in MS, most evidence shows a loss of white matter. In white matter astrocytes, densely positioned around the nodes of Ranvier, the beta2-adrenergic receptor (B2-adr) is decreased (
The effect of alpha- and beta-adrenergic blockade on daily rhythms of body temperature, urine production, and urinary 6-sulfatoxymelatonin of social voles Microtus socialis.
Comp Biochem Physiol A Mol Integr Physiol.2007; 148(Oct): 301-307
), suggesting that these may be co-ordinated with decreased astrocyte melatonin. Any such, decreases in astrocyte melatonin synthesis would contribute to lowering oligodendrocyte protection and the increased remyelination afforded by astrocytes (
Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP-9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia.
Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease.
Photoreceptor-specific expression, light-dependent localization, and transcriptional targets of the zinc-finger protein Yin Yang 1 in the chicken retina.
). This could suggest that the dampening effects of reactive astrocytes in the course of EAE may be via YY1 driven increased melatonin and/or NAS synthesis. This will be dependent on the availability of local melatonin precursors, including serotonin, suggesting that the reactivity process in astrocytes will be altered in conditions of decreased serotonin availability, as in depression.
The loss of astrocyte reactivity increases the infiltration of macrophages over T cells in EAE (
Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease.
), suggesting that astrocyte reactivity and fluxes may modulate the nature of the central immune cells present in EAE/MS. Melatonin is a significant driver of a phagocytic phenotype in many cell types, including macrophages, where nuclear factor-kappa beta (NF-κB) activation induces melatonin efflux, with resultant autocrine effects that decrease macrophage inflammatory responses, whilst increasing their phagocytic activity (
NF-kB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene.
). As such variation in local astrocyte melatonin production is likely to modulate the nature of chemoattracted immune cells and their responses in the course of demyelination and remyelination.
Studies looking for the factors regulating local melatonin and NAS are urgently required. Of the known regulators of astrocyte melatonin production, increased serotonin availability should modulate immune cell responses in MS and EAE, including in the nature of the macrophage response. To some degree this is supported by the efficacy of the monoamine oxidase inhibitor (MAOI), phenelzine, in EAE, where it decreases serotonin metabolism (
), thereby increasing serotonin availability for NAS and melatonin synthesis.
Interleukin (IL)-6 is classically associated with MS and the EAE model, where it can increase Th17 cell levels, thereby significantly contributing to immuno-inflammatory processes (
), suggesting a significant role for central IL-6 regulation in the etiology and course of MS. IL-6 is also a significant inducer of IDO, thereby increasing neuroregulatory TRYCATs and decreasing serotonin, NAS and melatonin. Melatonin epigenetically down-regulates IL-6 via the induction of methyl-CpG-binding protein 2 (MeCP2) (
). As well as decreasing IL-6, melatonin may also bind and regulate the activity and transcription of another Th17 cell modulator, the retinoic acid receptor-related orphan receptor-alpha (
), will decrease levels of the more damaging Th17 cells evident in MS and autoimmune disorders, partly via the regulation of IL-6.
Degenerated white matter leads to increased ingestion of lipids by macrophages and microglia. As to whether NF-κB induced melatonin in macrophages, via MeCP2 induction, drives the myelin-ingested macrophage suppression of IL-6, requires investigation. The ingestion of lipids by macrophages also increases cholesterol efflux via liver X receptor-beta (LXR-β) activation (
). It is unknown if LXR activation in macrophages and glia modulates or interacts with NAS and melatonin production. Should this occur, the wide protective effects of LXR activation in neurodegenerative conditions would then be modulated by variations in serotonin availability and NAS/melatonin efflux. Also myelin basic protein, a component of the myelin sheath, increases blood-brain barrier permeability (BBBp) (
Myelin basic protein induces inflammatory mediators from primary human endothelial cells and blood–brain barrier disruption: implications for the pathogenesis of multiple sclerosis.
Melatonin attenuates the postischemic increase in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator therapy following ischemic stroke in mice.
Apolipoprotein E ε4-positive multiple sclerosis patients develop more gray-matter and whole-brain atrophy: a 15-year disease history model based on a 4-year longitudinal study.
), which is in line with the ApoE4 allele being a susceptibility factor for Alzheimer’s disease, where it interacts with stress to heighten cognitive decline (
Accumulated and differential effects of life events on cognitive decline in older persons: depending on depression, baseline cognition, or ApoE epsilon4 status?.
J Gerontol B Psychol Sci Soc Sci.2011; 66(Jul): i111-i120
). This suggests that increased astrocyte melatonin synthesis by ApoE4 may be necessary to offset its neurotoxic effects. Depression and chronic stress, by decreasing serotonin availability for melatonin synthesis, may then differentially heighten ApoE4 neurotoxicity, including the severity of cognitive decline, and perhaps relapse risk, in MS.
2.5 Depression and melatonin in MS
White matter changes are also evident in depression, which highly associates with MS, with decreased levels of oligodendrocytes coupled to increased white matter hyperintensities evident at post-mortem and in neuroimaging studies of depressed patients (
). Depression is classically associated with decreased serotonin availability, suggesting a decrease in the synthesis of melatonin and NAS that, in turn, contributes to the increased immuno-inflammation evident in depressed patients (
), suggesting that variations in the availability of central serotonin for NAS and melatonin synthesis is likely to occur in both depressed and MS patients.
With melatonin modulating myelination and remyelination, depression is likely to be more than a simple psychiatric comorbidity of MS, but rather may be an integral part of the disease process, as suggested for other neurodegenerative conditions (
). Peripheral and central inflammation induced cytokines, including IL-1β, IL-6, IL-18 and TNF-α, but especially interferon-gamma (IFN-γ), increase IDO, thereby depleting serotonin, NAS and melatonin (
O&NS and peripheral inflammation induce IDO, thereby decreasing serotonin availability and increasing depression susceptibility, whilst concurrently increasing the likelihood of demyelination and lowering remyelination. Somatization strongly associates with depression, and is driven by increased IDO coupled to an increased kynurenine/kynurenic acid (KYNA) ratio (
). As well as having effects on peripheral sensory processing, kynurenine is also readily taken up over the BBB, increasing central TRYCATs that contribute to depression, somatization and fatigue (
). As to how relevant these changes are to the high levels of somatization, fatigue and pain reported in MS requires investigation.
2.6 Depression, gut permeability, melatonin and MS
Recent data shows an increase in gut permeability in depression, which can be driven by a number of factors, including diet, alcohol and stress associated cortisol (
Anderson G, Maes M. The gut-brain axis: the role of melatonin in linking psychiatric, inflammatory and neurodegenerative conditions. Adv Integr Med in press.
). Increased gut permeability allows gut bacteria and tiny bits of partially digested food to trigger an immune response, thereby contributing to systemic immuno-inflammation, which is thought to contribute to depression, including by increasing IDO and decreasing serotonin, NAS and melatonin availability. Such systemic inflammation can alter the macrophage and microglia phenotype in EAE (
), highlighting the relevance of systemic inflammation in the etiology and course of MS. The gut microbiome and gut permeability have recently been proposed to be major contributors to demyelinating disorders, especially MS (
). In the EAE model, increased gut permeability is an early event, prior to neurological symptoms, with heightened immuno-inflammatory activity contributing to these gut changes.
In this context, it is of note that melatonin is far more highly expressed in the gut, especially in enterochromaffin cells, than in the pineal gland (
). Melatonin significantly decreases gut permeability under a number of inflammatory conditions, including binge and chronic alcohol intake in rodents (
). As such, melatoninergic pathway susceptibility genes and decreased serotonin and melatonin in MS would be expected to contribute not only to circadian and local glia/immune cell melatonin synthesis, but also to gut melatonin synthesis and thereby to gut permeability mediated immuno-inflammatory processes. The ensuing increase in immuno-inflammatory processes, perhaps especially TNF (
), but also homocysteine, drive down pineal melatonin release, thereby impacting on a wide array of processes, including circadian, sleep, O&NS and immune cell activity, which are all altered in MS as well as in depression.
Emphasizing the occluded role of melatonin and NAS in different organs and cells, including in the pineal gland, gut and glia/immune cells, has implications for wider data in MS, as well as in the mechanisms of action of current treatments (see Fig. 2).
Fig. 2Serotonin is converted to N-acetylserotonin by AA-NAT, which is then enzymatically converted to melatonin by HIOMT. Melatonin is further degraded to a number of products, including AFMK and AMK, which have also anti-oxidant qualities. At least three cytochrome P450 enzymes (CYP1A1, CYP1A2, CYP1B2) convert melatonin to 6-hydroxymelatonin (6-Hmel), which can be further metabolized to 6-sulfomelatonin (6-Smel) by sulphotransferase (S-tran). Melatonin is also in equilibrium with 5-methyltryptamine (5-MeTryp), which is regulated by AA-NAT, aryl acylamidase and melatonin deacetylase (not shown). See main text for other acronyms.
3. Melatonin and NAS in wider MS associated pathways
A number of proteins and pathways have been associated with the etiology and/or course of MS, but have not been well integrated within current conceptualizations of this condition.
3.1 Leptin, obesity and melatonin
Increased obesity in early adulthood increases MS risk, suggesting a role for raised levels of leptin, leptin resistance and obesity induced inflammation in the etiology and course of MS (
In vitro effects of 5-hydroxytryptophan, indoleamines and leptin on arylalkylamine N-acetyltransferase (AA-NAT) activity in pineal organ of the fish, Clarias gariepinus (Burchell, 1822) during different phases of the breeding cycle..
), which, in the absence of leptin resistance, has neuroprotective effects. This is reciprocated, as leptin also increases pineal AA-NAT activity in fed but not fasted animals (
In vitro effects of 5-hydroxytryptophan, indoleamines and leptin on arylalkylamine N-acetyltransferase (AA-NAT) activity in pineal organ of the fish, Clarias gariepinus (Burchell, 1822) during different phases of the breeding cycle..
). In contrast, the loss of leptin signalling in EAE astrocytes worsens disease progression, being associated with increased leukocyte extravasation, demyelination and altered astrocyte effluxes (
). Given that the cAMP pathway is a significant regulator of pineal melatoninergic synthesis enzymes, it will be important to determine as to how leptin and leptin resistance modulate astrocyte NAS and melatonin production at different CNS sites, including as to how this is co-ordinated with other cAMP regulated processes in astrocytes, such as KYNA production. Central KYNA inhibits the alpha 7 nicotinic acetylcholine receptor activity, leading to decreased cortex glutamate, dopamine and acetylcholine release, in turn decreasing cognition (
Parada E., Buendia I., León R., Negredo P., Romero A., Cuadrado A., et al.Neuroprotective effect of melatonin against ischemia is partially mediated by alpha-7 nicotinic receptor modulation and HO-1 overexpression. J Pineal Res. in press.
). As such, cAMP induced leptin resistance will impact on cognition as well as wider astrocyte processes and effluxes. The association of leptin and leptin resistance in interaction with serotonin availability in modulating astrocyte NAS and melatonin production requires investigation.
3.2 Substance P
SubP is increased in depression and a number of neurodegenerative and psychiatric conditions (
). SubP effects are mediated via the neurokinin-1 receptor (NK-1r), which increases cAMP. The NK-1r is also upregulated by cAMP. SubP is a major activator of mast cells, thereby increasing BBBp, a major event in MS. In the EAE model of MS, SubP promotes the maintenance of inflammation (
). As with leptin, the significant role of SubP in the regulation of MS/EAE is long recognised but not integrated into current conceptualizations of the biological underpinnings of MS. As to how SubP modulates astrocyte and gut NAS and melatonin synthesis requires investigation, including within white matter astrocytes and in conditions of increased cAMP/Epac in leptin resistance.
3.3 Mitochondria, melatonin and MS
Accumulating data shows mitochondrial defects and an energy deficient state in the pathogenesis of MS (
). In myelinated axons over 90% of mitochondria are located within juxtaparanodal and internodal axoplasm. Following demyelination the number of mitochondria increases, which is maintained even after remyelination. It remains to be determined as to whether these changes in axonal mitochondria content have any impacts on axonal mitochondria melatonin synthesis and as to whether an increased astrocyte production of melatonin would normalize axonal mitochondria number and functioning. Deficits in mitochondrial respiratory chain function are evident in lesion associated oligodendrocytes, hypertrophied astrocytes and axons in MS (
Quantitative ultrastructural analysis of a single spinal cord demyelinated lesion predicts total lesion load, axonal loss, and neurological dysfunction in a murine model of multiple sclerosis.
), suggesting that local melatonin synthesis will have beneficial effects in a diverse range of lesion-associated cells, in part via the optimization of mitochondrial functioning.
Damage to myelin and mitochondria are partly mediated by increased microglia and macrophage reactivity (
), which the stimulation of the autocrine and paracrine effects of astrocyte and macrophage local melatonin synthesis would also decrease. As such local melatonin may inhibit the immune cell activations that drive mitochondrial damage, as well as increasing mitochondrial functioning per se, in different lesion-associated cells.
O&NS driven lipid peroxidation, readily measured by products such as 4-hydroxy-2-nonenal (4HNE) has been proposed as an early event in the etiology of MS (
). Sirtuin-3 is mitochondria located and a significant regulator of mitochondrial functioning. Sirtuin-3, like sirtuin-1, is increased by nicotinamide. Melatonin is a significant inducer of sirtuin-1 (
), suggesting that it will have concurrent impacts on levels of sirtuin-3. Both these sirtuins are longevity associated, with sirtuin-1 also having positive mitochondria regulating effects via its activation of the master mitochondrial co-ordinator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α). The role of altered sirtuins in MS has still to be fully examined, with data showing that sirtuin-1 is expressed in a number of lesion-associated cells of MS patients, including CD4(+) and CD68(+) leukocytes, as well as in oligodendrocytes and astrocytes (
). These authors also showed a statistically significant decrease in sirtuin-1 mRNA and protein expression in peripheral blood mononuclear cells during relapses versus levels in controls and in stable MS patients.
There is a growing interest in the role of microRNAs (miRNA) in MS (
CIHR/MSSC new emerging team grant in clinical autoimmunity; MSSRF Canadian B cells in MS team. A novel microRNA-132-surtuin-1 axis underlies aberrant B-cell cytokine regulation in patients with relapsing-remitting multiple sclerosis.
). As such, many of the effects of melatonin, including in the regulation of sirtuins and mitochondrial functioning, may be in association with miRNA alterations.
If indeed astrocytes have a co-ordinating and perhaps controlling role in their interactions with neurons and other CNS cells (
Neuronal-immune interactions in mediating stress effects in the etiology and course of schizophrenia: role of the amygdala in developmental co-ordination.
), the state of astrocyte melatonin and NAS synthesis may be relevant as to how neighbouring cells are strengthened or weakened, as in the case of neurons and oligodendrocytes, or have their reactivity threshold regulated, as in the case of microglia and infiltrating leukocytes. As such B-adr, ApoE4 and serotonin availability as well as other yet to be identified NAS and melatonin regulators in white matter astrocytes may be having significant impacts on oligodendrocyte survival and microglia reactivity in the etiology and course of MS, partly via astrocyte melatonin’s regulation of mitochondria functioning in these cells.
Overall, given the high accumulation of exogenous and extracellular derived melatonin around mitochondria, it is likely that extracellular sources of melatonin supplement mitochondrial sources with positive impacts on mitochondrial functioning and compartmental anti-oxidant co-ordination. As indicated above this is likely to be co-ordinated with the regulation of sirtuins. This may allow astrocytes to have a integrating and regulatory role in the CNS, in part via variations in NAS and melatonin efflux.
4. Melatonin and MS treatments
Given the wide range of melatonin’s effects in different cell types and tissues, it is likely that melatonin will be relevant to the effects of current medications, as well as to the development of new treatments.
4.1 Fingolimod
Fingolimod is a recently developed treatment for MS, where its benefits include decreasing the thymic egress of T cells (
). Phosphorylated fingolimod binds to four of the five sphingosine-1-phosphate (S1P) receptors, with its regulation of astrocyte S1P1r being crucial to its efficacy in EAE (
). S1Pr activation is intimately involved in the activation of glia, where S1P1r activation leads to Rac1, which can activate NADPH Oxidase, leading to superoxide release, which is rapidly converted to hydrogen peroxide, in turn leading to neutral sphingomyelinase (SMase), ceramide and lipid raft reorganization (
Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and alpha-actinin.
). Fingolimod decreases the induction of SMase and ceramide in reactive astrocytes, thereby decreasing levels of S1P availability, as well as decreasing BBBp (
). As to whether fingolimod modulates the maintenance of astrocyte reactivation, either directly via impacts on S1P3r or via inhibiting the initial role of S1P1r in driving lipid raft plasticity that includes the shifting of the S1P3r into rafts, requires investigation. Certainly part of the efficacy of fingolimod is mediated by its regulation of astrocyte reactivity (
N-Acetylserotonin increases cell proliferation and differentiating neuroblasts with tertiary dendrites through upregulation of brain-derived neurotrophic factor in the mouse dentate gyrus.
), suggesting that variations in glia NAS and NAS/melatonin ratio may be more important to TrkB activation and myelination levels. BDNF levels are increased in the cerebral spinal fluid in MS (
), likely indicative of processes driving increased myelination, although site and cellular source of production have still to be ascertained. Serum levels of BDNF are also increased and further raised by IFN-β treatment (
). As such, TrkB activation is an important inducer of oligodendrocyte myelination and may be activated by NAS or BDNF, including NAS induced BDNF. The impact of fingolimod on glia NAS, melatonin and NAS/melatonin ratio requires investigation, including as to whether factors increasing serotonin availability, such as SSRIs and MAOIs, would be useful adjunctives to fingolimod. It is of note that fingolimod, as with sphingosine, can bind and regulate the function of 14-3-3 (
), suggesting fingolimod impacts on the melatoninergic pathways.
4.2 Glatiramer acetate
Glatiramer acetate (GA) is another commonly used treatment in MS, although it mode of efficacy is still under investigation and may involve the induction of regulatory CD8+ T cells (
), where is actions, like fingolimod in this model, are thought to be mediated via increased BDNF in neurons. However, given that the effects of MeCP2 knockout in driving Rett syndrome features seem to be mediated in astrocytes and microglia (
). Some of their effects may be mediated by the regulation of melatonin, which is also significantly decreased, as well as being a genetic susceptibility factor, in bipolar disorder (
), which the authors show is associated with improved sleep and decreased fatigue. Fatigue is an important debilitating symptom in MS and, as highlighted above, has biological underpinnings that closely link it to depression (
), suggesting that efficacy may also occur by increasing melatonin’s precursor, NAS, thereby activating BDNF’s TrkB receptor. Overall, as with other MS treatments, some of the efficacy of IFN-β may be mediated by the regulation of the melatoninergic pathways.
5. Conclusions
The occluded role of NAS and melatonin in the etiology, course and treatment of MS is highlighted above. The targeting of astrocyte, gut and immune cell NAS and melatonin synthesis are likely to be significant pharmacological treatment goals in MS.
Conflicts of interest
Neither author has any relevant conflicts of interest to declare.
References
Akpinar Z.
Tokgöz S.
Gökbel H.
Okudan N.
Uğuz F.
Yilmaz G.
The association of nocturnal serum melatonin levels with major depression in patients with acute multiple sclerosis.
Anderson G, Maes M. The gut-brain axis: the role of melatonin in linking psychiatric, inflammatory and neurodegenerative conditions. Adv Integr Med in press.
Neuronal-immune interactions in mediating stress effects in the etiology and course of schizophrenia: role of the amygdala in developmental co-ordination.
Photoreceptor-specific expression, light-dependent localization, and transcriptional targets of the zinc-finger protein Yin Yang 1 in the chicken retina.
Melatonin attenuates the postischemic increase in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator therapy following ischemic stroke in mice.
Accumulated and differential effects of life events on cognitive decline in older persons: depending on depression, baseline cognition, or ApoE epsilon4 status?.
J Gerontol B Psychol Sci Soc Sci.2011; 66(Jul): i111-i120
Myelin basic protein induces inflammatory mediators from primary human endothelial cells and blood–brain barrier disruption: implications for the pathogenesis of multiple sclerosis.
The fat mass and obesity-associated FTO rs9939609 polymorphism is associated with elevated homocysteine levels in patients with multiple sclerosis screened for vascular risk factors.
In vitro effects of 5-hydroxytryptophan, indoleamines and leptin on arylalkylamine N-acetyltransferase (AA-NAT) activity in pineal organ of the fish, Clarias gariepinus (Burchell, 1822) during different phases of the breeding cycle..
Apolipoprotein E ε4-positive multiple sclerosis patients develop more gray-matter and whole-brain atrophy: a 15-year disease history model based on a 4-year longitudinal study.
The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression.
CIHR/MSSC new emerging team grant in clinical autoimmunity; MSSRF Canadian B cells in MS team. A novel microRNA-132-surtuin-1 axis underlies aberrant B-cell cytokine regulation in patients with relapsing-remitting multiple sclerosis.
NF-kB drives the synthesis of melatonin in RAW 264.7 macrophages by inducing the transcription of the arylalkylamine-N-acetyltransferase (AA-NAT) gene.
Parada E., Buendia I., León R., Negredo P., Romero A., Cuadrado A., et al.Neuroprotective effect of melatonin against ischemia is partially mediated by alpha-7 nicotinic receptor modulation and HO-1 overexpression. J Pineal Res. in press.
Quantitative ultrastructural analysis of a single spinal cord demyelinated lesion predicts total lesion load, axonal loss, and neurological dysfunction in a murine model of multiple sclerosis.
Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and alpha-actinin.
Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP-9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia.
Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes.
Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease.
N-Acetylserotonin increases cell proliferation and differentiating neuroblasts with tertiary dendrites through upregulation of brain-derived neurotrophic factor in the mouse dentate gyrus.
The effect of alpha- and beta-adrenergic blockade on daily rhythms of body temperature, urine production, and urinary 6-sulfatoxymelatonin of social voles Microtus socialis.
Comp Biochem Physiol A Mol Integr Physiol.2007; 148(Oct): 301-307
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