Vitamin D in Sleep Disorders

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1		Oliviero Bruni	+ 2663 word(s)	2663	2022-02-10 05:12:50

This entry is adapted from the peer-reviewed paper 10.3390/ijms23031430

Vitamin D is a fat-soluble vitamin, mainly synthesized in the body through ultraviolet B (UVB) exposure on the skin or taken orally through food and/or supplements.

vitamin D sleep insomnia obstructive sleep apnea

1. Introduction

Vitamin D is a fat-soluble vitamin, mainly synthesized in the body through ultraviolet B (UVB) exposure on the skin or taken orally through food and/or supplements. According to the definition of the Endocrine Society we can define the following categories: deficiency (<20 ng/mL); insufficiency (between 20 and 29 ng/mL); and sufficiency (≥30 ng/mL) ^[1]. Vitamin D deficiency/insufficiency is a global epidemic, estimated to affect over one billion people worldwide ^[2], including children ^[3].

Even if its principal function is bone homeostasis regulation, vitamin D is also involved in several other conditions, such as cardiovascular diseases, cancer, diabetes mellitus, and autoimmune disorders ^[4]; recently, an increasing number of studies are showing the link between vitamin D and sleep. Low vitamin D levels have been reported to be associated with shorter sleep duration ^[5], and adequate levels of vitamin D seem to be necessary for the maintenance of sleep, reducing the number of nocturnal awakenings ^[6].

Although the exact mechanism by which vitamin D affects sleep regulation is still unclear, the key to this link seems to be the expression of vitamin D receptors (VDRs) in areas of the brainstem that are involved in sleep regulation ^[7]^[8]. Previous studies have shown that VDRs are expressed in both developing and adult rat brains ^[9]; in the human brain, the VDR distribution has been described as strikingly similar to that detected in rodents ^[10]. VDRs are expressed in the cortical and subcortical areas involved in sleep control, such as: (a) the prefrontal cortex, which mediates normal sleep physiology, dreaming, and sleep-deprivation phenomena and is activated during Non-Rapid Eye Movement (NREM) and deactivated during Rapid Eye Movement (REM) sleep ^[11]; (b) the cingulate gyrus, which is activated by breathing and blood pressure changes affected by sleep apnea ^[12]; (c) the hippocampal dentate gyrus, where neurogenesis is significant in adults ^[13] and is influenced by sleep deprivation, that reduces proliferation of progenitor cells ^[14]; (d) the caudate nucleus, which is downregulated in disturbed sleep and insomnia, especially during executive functioning ^[15]; (e) the lateral geniculate nucleus, which plays a major role in ponto-geniculo-occipital waves during REM sleep ^[16]; and (f) the substantia nigra, where the dopaminergic pathway is closely involved in the regulation of the sleep–wake cycle and is implied in idiopathic REM sleep behavior disorder ^[8]^[17].

Vitamin D might exert its effects on neurocognition based on several mechanisms mediated by sleep, including induction of neuroprotection, modulation of oxidative stress, regulation of calcium homeostasis, and suppression of inflammation ^[18]. Vitamin D has been proposed to act as a membrane antioxidant. In fact, it increases the gene expression levels of antioxidants agents ^[19] and decreases cytokine generation via inhibitory effects on the activation and expression of nuclear factor kappa B (NF-κB) and other related genes ^[20].

Similar to the other steroid hormones, vitamin D binds to its nuclear receptors, VDRs, and retinoid X receptors (RXRs), to effect transcriptional changes. Pertinent to sleep, VDRs and RXRs have been shown to downregulate transcription of RelB gene, a gene encoding a family of transcription factors; collectively referred to as NF-κB ^[21] that plays a pivotal pro-inflammatory role, both in terms of the production of sleep-regulating substances, such as IL-1 and tumor necrosis factor alpha (TNF-a), but also in terms of the selective activation of inflammatory pathways known to occur in the setting of intermittent hypoxia, as in obstructive sleep apnea (OSA) ^[22]^[23].

Since the vitamin D receptor is expressed on immune cells (B cells, T cells, and antigen presenting cells) and these immunologic cells are all capable of synthesizing the active vitamin D metabolite, vitamin D can modulate the innate and adaptive immune responses. Deficiency in vitamin D is associated with increased autoimmunity as well as an increased susceptibility to infection ^[24].

On the other hand, substances of the immune system, in particular the cytokines IL-1 and TNF, and prostaglandin (PG) D2 are involved in the regulation of physiological sleep in animals, and sleep duration (short and long) and disturbances (including insomnia) are linked to dysregulation of inflammatory markers, immune cell counts, and cellular aging markers. In disorders characterized by immune dysregulation, immune-therapy may not only be used to improve disease activity, but also to directly improve sleep ^[25]^[26]. Similarly, vitamin D supplementation should be considered for the prevention and treatment of immune diseases as well as for improving sleep quality.

Melatonin has also been suggested to act as a mediator of the neuro-immunomodulatory properties of vitamin D ^[27]. Alongside Vitamin D, melatonin participates in the regulation of circadian rhythms and sleep, immune response, and bone metabolism ^[28]^[29]. Melatonin and its metabolites exhibit a wide spectrum of both direct and indirect physiological effects in humans ^[30]^[31]^[32]^[33]^[34]. First, these compounds scavenge free radicals and other non-radical Reactive Oxygen Species/Reactive Nitrogen Species (ROS/RNS) directly, reducing the level of oxidative stress and, thus, show antioxidant abilities preventing inflammation. Second, these biomolecules participate in immunomodulation, improve immune defense, and exhibit other physiological activities, e.g., regulate circadian rhythms, body temperature, increase physical performance and glucose uptake in muscles, and prevent against lipid accumulation, among others ^[35]^[36]^[37]^[38]^[39]. Importantly, melatonin is effective in adjusting the sleep–wake cycle and improving the quality of sleep. Melatonin stabilizes circadian rhythms and exerts its chronobiotic effects by acting on the plasma membrane trough G protein-dependent receptors type 1 and type 2 called MT1 and MT2, and its rhythmic release is regulated by a central circadian rhythm generator ^[40].

1.1. Vitamin D and the Serotonergic System

Soon after the time of its discovery, over 40 years ago, the serotonergic system was implicated in the regulation of the sleep–wake cycle. While early studies indicated that serotonin (5-HT) was associated with the initiation and maintenance of sleep, later studies indicated that serotonergic neurons also play a role in inhibiting sleep. The complex effects of 5-HT on the regulation of sleep are due in part to the fact that 5-HT can act at different areas of the brain that have been associated with the control of sleep and wake.

In addition, the recent discovery of multiple 5-HT receptors within the mammalian brain has led to the finding that different 5-HT receptors are selectively involved in the regulation of the different sleep states ^[41]^[42]. Based on electrophysiological, neurochemical, genetic, and neuropharmacological approaches, it is currently accepted that 5-HT functions predominantly to promote wakefulness and to inhibit REM sleep. However, under certain circumstances this neurotransmitter contributes to the increase in sleep propensity ^[43]. Serotonin is synthetized in the brain from its precursor tryptophan, an essential amino acid obtained from the diet ^[44]^[45] through the action of tryptophan hydroxylase and participates in the regulation of circadian rhythms ^[46]^[47]^[48].

Vitamin D plays a key function in the regulation of the serotonergic pathway ^[18]^[49]^[50] and in melatonin production, confirming the importance of vitamin D in sleep but also in mood regulation ^[50]^[51]. Furthermore, the presence of VDRs in limbic structures, including hippocampus, amygdala, and prefrontal cortex, suggests that vitamin D could be also associated with the regulation of mood and emotional behavior ^[52]. In detail, vitamin D can influence the serotoninergic pathway in the brain and in the peripheral tissues binding the vitamin D response elements (VDREs) on the tryptophan hydroxylase genes (THP1 and THP2), involved in serotonin production. Vitamin D inhibits the expression of THP1 in the peripheral tissues and increases the expression of THP2 in the brain ^[50]^[53]. A special isoform of the enzyme tryptophan hydroxylase, TPH2, converts the amino acid tryptophan into 5-hydroxytryptophan, a precursor of serotonin. TPH2 is entirely restricted to neurons of the raphe nuclei and the enteric nervous system and is the enzyme responsible for producing all of the serotonin in the brain ^[54].

Serotonin in the brain promotes prosocial behavior and correct assessment of emotional social cues ^[55]. This seems to explain the link between vitamin D levels, serotonin, sleep, and mood regulation ^[53]. Regarding sleep, vitamin D exerts an important function acting on the THP1 expression in the pineal gland. Through THP1 expression, the pineal gland converts serotonin into melatonin during evening and nighttime ^[56]^[57]. According to the daily variation in natural light exposure ^[58], the variation of serum vitamin D levels, from relatively high during daytime to relatively lower during nighttime, may be necessary for optimal TPH1 expression in the pineal gland for melatonin regulation. It may be the case that disturbances in these daily variations could have an influence on sleep timing and/or quality ^[51]. In addition, vitamin D regulates the conversion of tryptophan into 5-HTP ^[50] and regulates the production of melatonin also for its action on tryptophan hydroxylase ^[59].

1.2. Vitamin D and the Dopaminergic System

On the other hand, vitamin D plays an important function in the dopaminergic system participating in the regulation of the nervous system development and function ^[60]. Dopamine neurons in the midbrain and their target neurons in the striatum were shown to express vitamin D receptor proteins, and vitamin D receptors are present in the nucleus of tyrosine hydroxylase-positive neurons, in both, human and rat substantia nigra ^[61]. Oran et al. ^[62], observed how rat primary dopaminergic neurons had a dose-responsive increase in number when vitamin D3 (the hormonally active form of vitamin D) was added to culture media, suggesting that vitamin D might increase the number of dopaminergic neurons by upregulating the expression of glial-derived neurotrophic factor. In addition, it has been reported that vitamin D affects the nigrostriatal dopaminergic pathway by increasing the levels of dopamine or its metabolites and by protecting dopaminergic neurons against toxins ^[63]^[64].

Treatment with vitamin D could increase dopamine concentration and its metabolites in the substantia nigra and protect mesencephalic dopaminergic neurons against toxins that cause a decrease in the glutathione content, which might lead to selective dopaminergic neuron death ^[65]^[66]. In fact, it seems that vitamin D may participate in the antioxidant mechanism controlling brain homeostasis ^[67]. Vitamin D has been recently reported to enhance the intracellular glutathione concentration in the central nervous system ^[68].

Exposing rat cultured mesencephalic neurons for 24 h to a mixture of L-buthionine sulfoximine (BSO) and 1-methyl-4-phenylpyridium ions (MPP) resulted in a relatively selective damage to dopaminergic neurons ^[69]. This damage was accompanied by a reduction in intracellular glutathione levels. Low doses of Vitamin D3 protect cultured dopaminergic neurons against this toxicity. Generation of ROS by this toxicity has been attenuated in cultures being pretreated with low concentrations of Vitamin D3. These data suggest that low doses of Vitamin D3 are able to protect mesencephalic dopaminergic neurons against BSO/MPP induced toxicity that causes a depletion in glutathione content ^[63].

It is interesting to notice that dopaminergic dysfunction, together with iron dysregulation are the main pathophysiologic mechanisms involved in the development of Restless Legs Syndrome (RLS) ^[70]. Vitamin D may be involved in the pathogenesis of RLS because of its effects on the dopaminergic system, through VDRs present in the nucleus of neurons that are positive for tyrosine-hydroxylase in the substantia nigra. In fact, Vitamin D deficiency can be considered a risk factor for RLS. The incidence of RLS, indeed, is increased in adult patients with vitamin D deficiency ^[61]^[70]^[71] and a significant inverse correlation was found between vitamin D levels and severity of RLS ^[72]. Interestingly, infants diagnosed with iron-deficiency anemia simultaneously show low levels of serum vitamin D ^[73]. The addition of vitamin D to their diet might improve blood and tissue iron concentration.

Therefore, due to his effect at the gene and receptor levels, it is not surprising that vitamin D might exert a clinical effect on sleep and sleep disorders. The impact of vitamin D on sleep has been well described in adults; its deficiency has been associated with multiple sleep disorders such as OSA, RLS, changes in sleep duration, and worsening of sleep quality ^[22]. Adult patients return to normal sleep cycles with vitamin D levels at 60–80 ng/mL suggesting the need to reach levels higher than the normal accepted values of 30 ng/mL for the treatment of sleep disorders.

2. Vitamin D and Obstructive Sleep Apnea (OSA)

Obstructive sleep apnea (OSA) in children is a disease characterized by recurrent episodes of partial or complete upper airway obstruction associated with arousals, awakenings, and/or oxyhemoglobin desaturations during sleep. It may also be associated with disruption of ventilation and normal sleep patterns ^[74]. If inadequately diagnosed/treated in children, it can be associated with behavioral problems, learning difficulties, cardiovascular complications, and growth retardation ^[75]^[76]. OSA is a relatively common disorder in childhood affecting up to 3% to 4% of all children. Two studies (Kheirandish-Gozal et al. ^[77] and Ozgurhan et al. ^[78]) demonstrated a linear relationship between vitamin D levels and risk of OSA. In their study, Kheirandish-Gozal et al. ^[77] hypothesized that OSA might be associated with lower vitamin D levels and increased risk of metabolic dysfunction and systemic inflammation.

The role of vitamin D in systemic inflammation has been investigated in adults. Lower vitamin D serum levels have been associated with an increased risk of respiratory infection and an increased incidence of allergic rhinitis. Recurrent respiratory infections and immune system dysregulation may promote the development of tonsillar hypertrophy and chronic rhinitis, both of which increase the risk of OSA. Furthermore, OSA has been described as a low inflammatory state disease and vitamin D might be helpful by inhibiting the secretion of proinflammatory T-helper cell 1 cytokines IL-2, IFN-g, and TNF-a and enhancing the production of anti-inflammatory Th2 cytokines (IL-3, IL-4, IL-5, and IL-10) ^[79].

In another study, Ozgurhan et al. ^[78], evaluated the risk of OSA in two groups of children according to their levels of vitamin D: a low-level vitamin D group (<20 ng/mL) and a control group (>20 ng/mL). The risk of developing OSA as determined by the Berlin Questionnaire was found to be statistically higher in the low-level vitamin D group when compared with the control group (p = 0.030). The percentage of patients at high risk of developing OSA was 14.16% for the low-level vitamin D group and 5.83% for the control group.

Another interesting study by Zicari et al. ^[80] assessed the association between mean platelet volume (MPV), vitamin D, and C Reactive Protein (CRP) in patients with OSA, primary snoring (PS), and a control group. MPV levels were higher in subjects with OSA and PS when compared to controls; platelet count (PLT) and CRP levels were also higher while vitamin D levels were lower in children with OSA and PS when compared to the control group.

Other studies hypothesized that vitamin D might play a role in modulating behavioral and cognitive dysfunctions in children with OSA ^[81]^[82]. Cui et al. ^[83] found that triglycerides, total cholesterol, low-density lipoprotein, and body mass index of the OSA group were clearly higher than those of the control group, while the level of serum vitamin D and high-density lipoprotein was clearly lower. The supplementation of vitamin D determined an improvement of the vitamin D level and a decrease in the indexes of conduct problems, learning problems, and hyperactivity. Vitamin D supplementation had no therapeutic effect on obesity and dyslipidemia of OSA children but had obvious protective and improving effects on neuron damage caused by hypoxia ^[84].

Another interesting fact that emerges from our review is that the level of vitamin D in parents can play a role in determining the blood levels of vitamin D in children with snoring problems. This correlation was analyzed by Barceló et al. ^[85] who assessed the interrelationship between serum vitamin D levels and metabolic profiles, sleep parameters and paternal and maternal vitamin D status in a sample of snoring children referred to a sleep unit. Significant associations were found between serum vitamin D concentrations in children who snored and their parents. The prevalence of vitamin D insufficiency of the parents varied significantly based on the children’s vitamin D status and was greater in parents whose children had vitamin D insufficiency: overall in 64.9% of fathers and 63.2% of mothers. In children with vitamin D deficiency, an inverse correlation between the apnea–hypopnea index and respiratory arousal index and vitamin D concentrations was also observed. This study suggests that a familial status of vitamin D could be used as an indicator for the early identification of children at risk of unhealthy sleep and/or metabolic complications.

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