Effect of vitamin D on brain development during ontogenesis: literature review

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Abstract

The article presents a review. Information on metabolism of vitamin D and its significance in the formation of the brain in the prenatal and postnatal periods is given. An up-to-date data regarding the effect of vitamin D on neurogenesis, activity of neurotransmitter systems, formation of cognitive status and quality of emotional state in children and adolescents is analyzed. The role of vitamin D in pathogenesis of autistic spectrum disorders, resistant forms of epilepsy, deviant variants of development in children is discussed.

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Modern neuroscience studies various pathogenetic and sanogenetic aspects in the functioning of the brain. Metabolic factors play a significant role in the ontogenesis of the central nervous system, in particular, the optimal content of trace elements and vitamins in the body and their diverse biological significance.The study of vitamin D metabolism has been going on for more than 100 years around the world. The British pharmacologist Edward Mellanb discovered vitamin D in 1919. The structure of vitamin D was described by the German scientist Adolf Windaus [1]. Up until the 80s of the last century, the only purpose of vitamin D was the prophylaxis and treatment of rickets in children. However, after the discovery of vitamin D receptors in various organs and tissues, interest in the scientific community increased significantly [2, 3]. Currently, the pleiotropic and extra-skeletal effects of vitamin D are being investigated more and more. The relationship between vitamin D deficiency and various diseases from the cardiovascular, endocrine, nervous, immune and other systems in children has been proven. [2].At the same time, the results of epidemiological studies indicate that currently at least 30-50% of the population in various countries and regions of the world have low levels of vitamin D in the blood [4].In total, six sterols belong to the vitamin D group. But two of them play a key role in the human body: vitamin D2  ergocalciferol and vitamin D3  cholecalciferol. The main sources of vitamin D2 are fish, milk, as well as bread and mushrooms. Once in the body, vitamin D2 is absorbed in the small intestine in the presence of bile, then it is included in the composition of chylomicrons and then goes through the stages of metabolism similar to cholecalciferol. [5]. Due to the extremely low vitamin activity of ergocalciferol, it is practically not used in medicinal form.Vitamin D3 (cholecalciferol) is formed in the epidermis of the skin from previtamin D (7dehydrocholesterol) when exposed to UV. Further, cholecalciferol binds to vitamin D-binding protein and most of it (70%) from the bloodstream enters the liver, and the remaining part enters fat cells, and forms a depot of vitamin D [6].Vitamin D metabolism is a long chain. Initially, it creates a complex with vitamin-D-binding protein (VDBP) and albumin, and is transported to the liver. And in the liver, by hydroxylation, they turn into the first active metabolite  25 (OH)D (25-hydroxyvitamin D  calcidiol) [7]. 25 (HE)D  is the main circulating metabolite of vitamin D, its life span is about 3 weeks. Therefore, it is considered the most accurate indicator of vitamin D levels. Its concentration in healthy children is in the range of 15-40 ng/ml. A decrease of this metabolite to 10 ng/ml indicates a D—deficiency. The level of 5 ng/ml and below corresponds to the state of D-vitamin deficiency [8, 9]. Vitamin D absorption also depends on adequate digestion and assimilation of dietary fat [10].At the second stage of metabolism, 25(OH)D3 is transferred to the kidneys using transport proteins (VDBP). The resulting complex 25(OH)D3/VDBP interacts with cells of the proximal tubules, which reabsorb 25(OH)D3 from the glomerular filtrate. Further, 25(OH)D3 is hydroxylated to the biologically highly active metabolite calcitriol (1,25(OH)2D and 24.25(HE)2D). According to modern data, 1.25(OH)2D is a hormone that in its activity is from 10 to 100 times (according to various data) exceeds the activity of 25 (OH)D [11]. 25(OH)D3 is able to convert into 1,25(OH)2D3 in immune, epithelial cells of the body, bone tissue, vascular endothelium, parathyroid glands and intestinal mucosa [12]. Thanks to the education of 24.25(HE)2D there is a main way of catabolism and excretion of vitamin D derivatives in the body [13]. The targets of active vitamin D3 metabolites are vitamin D3 receptors (VDR  vitamin D receptor), which are present in more than 38 organs and tissues of the body and provide its pleiotropic effect [14, 15].Vitamin D has important biological significance at various stages of life. It plays an important role during pregnancy, it has a beneficial effect on the mother-placenta-fetus system, participating in: the implantation process [16, 17]; in the formation of the placental complex [18]; regulation of an adequate immune response to the emerging pregnancy [19]; in the normal development of the fetal bone and cartilage skeleton [20]; in providing local immunity in the vagina [21]. Prenatal vitamin D deficiency may increase the risk of fetal development of: congenital cataracts, autoimmune diseases, type I diabetes, cardiovascular and atopic diseases [22, 23].Vitamin D in a pregnant woman affects the neurocognitive development of the fetus. A low level in the mother leads to speech disorders and language difficulties later in the offspring. [24]. Babies born to women with a deficiency of 25(OH)D (<15 ng/ml), according to generally accepted development assessment scales, had significantly low indicators of speech skills compared with children born to mothers with normal vitamin D levels (>30 ng/ml). [25, 26]. A decrease in the level of 25-hydroxyvitamin D in the mother at an early stage of pregnancy increases the risk of developing ADHD in the child [27]. In the experiment, vitamin D deficiency during pregnancy leads to an increase in impulsive behavior of offspring against the background of the absence of inhibitory control [28].The experiment proved that prenatal vitamin D deficiency is associated with disorders of synaptic plasticity in the dentate gyrus, in particular, led to a significant deterioration of latent inhibition and violations of long-term potentiation in the hippocampus. The hippocampus and its dentate gyrus are of great importance for supporting memory function [29]. It is assumed that vitamin D directly affects the differentiation of oligodendrocyte axons, a relative lack of vitamin D can enhance oligodendroglia apoptosis. Vitamin D deficiency during pregnancy in the last two semesters increases the risk of multiple sclerosis in infants [30, 31].Vitamin D exerts its influence on brain development not only by directly influencing cellular processes, but also by influencing gene expression through VDRE. [32]. On the part of the nervous system, vitamin D receptors have been found in neurons and glial cells, and their highest expression is observed in the hippocampus, hypothalamus, thalamus and subcortical gray nuclei, as well as in the substantia nigra [33]. Vitamin D plays an important role in proliferation and differentiation, signal transmission in synapses, the state of calcium channels, as well as in neurotrophic and neuroprotective action. [34] The neuroprotective effect of vitamin D is to influence the synthesis of neurotrophin, which is an endogenous regulator of development (neuro- and sanoptogenesis, neuroplasticity) and participates in the regeneration of the nervous system. Vitamin D also contributes to the synthesis of neurotransmitters, in particular acetylcholine, dopamine, serotonin and gamma-butyric acid [35].The effect of vitamin D on dopamine biosynthesis is associated with the activation of gene expression of the main enzyme of dopamine biosynthesis  tyrosine hydroxylase (TN gene). With dopamine deficiency in children, there is a slowness of cognitive processes with increased inertia., switching and maintaining attention, fine motor skills suffer, which negatively affects the psychorechological development and the acquisition of school skills. In adolescence, changes in metabolism are associated with the formation of addictions [36]. In addition, vitamin D protects dopaminergic neurons from the neurotoxic effects of glutamate [37].Vitamin D affects the metabolism of other monoamines in the brain. In the experiment, hypovitaminosis D was associated with a decrease in the concentration of endogenous norepinephrine due to a violation of the regulation of calcium levels in neurons. As a result, there is a decrease in cognitive potential, the formation of alexithymia is facilitated, the emotional background is impoverished [38]. The modulating effect of vitamin D on the sympathetic part of the autonomic nervous system has been demonstrated [39]. As well as prevention of oxidative tissue damage. [40, 41]. Thus, part of the neurophysiological effects of vitamin D are due to genomic mechanisms - interactions of the vitamin D receptor (VDR) with genomic DNA, maintenance of genome stability in cell division cycles, DNA repair, chromosome restructuring, as well as support for protein synthesis and degradation, immune modulation, regulation of embryogenesis and energy metabolism [42].The connection of the variety of biological effects of vitamin D with psychoemotional and cognitive status is becoming more obvious. Optimal brain development and functioning occurs when vitamin D levels in the blood exceed 30 ng/ml [43]. However, modern screening studies in the territory of the Russian Federation have demonstrated a normal vitamin D content in the blood of less than 10% of children of different age groups [44]. Levels 25(OH)Serum D in children with deviant developmental variants is significantly lower than in normotypic peers. Correlations between level 25(OH) have been establishedD and the results of the Wexler scale and the Benton visual memory test (BVRT  Benton visual retention test) [45].It has been demonstrated that vitamin D provision normalizes mood swings in the autumn-winter period with seasonal affective disorder, which includes hypersomnia, lethargy, circadian rhythm disorders, excessive need for carbohydrates [46]. There is evidence of a correlation between a low level of 25(OH)D3 in adolescents with depression and the frequency of suicide [47]. Some studies suggest a link between vitamin D and headache; however, the underlying physiological mechanisms are unclear. In general, there is insufficient evidence to recommend vitamin D supplements to all patients with headache, however, the problem requires further study [48, 49].
Significant vitamin D deficiency in children plays the role of a risk factor in the etiopathogenesis of autism spectrum disorders (ASD) in children [50, 51]. Two open studies have shown that a high dose of vitamin D improves the main symptoms of ASD in about 75% of children. Vitamin was applied at a dose of 300 IU/kg/day with a maximum of 5000 IU/day [52]. Other studies confirm that taking vitamin D3 is a safe and cost-effective form of treatment that can significantly improve the outcome of some children with ASD, especially at an early age [53].The effect of vitamin D on the course of forms of epilepsy resistant to antiepileptic therapy (AET) is being studied. The initial report of an ongoing experimental study in the USA of the oral administration of vitamin D3 at a dose of 5000 IU/day in patients with resistant epileptic seizures indicates that with the appointment of high doses of vitamin D (up to 5000 IU/day), the average frequency of seizures decreased from 5.18 seizures per month to 3.64 seizures per month after 6 weeks and to 4.2 seizures in a month after 12 weeks [54]. There is enough accumulated information about the role of vitamin D in the pathogenesis of multiple sclerosis (MS) [55]. Epidemiological analyses confirm that there is a direct causal relationship between latitude, sun exposure, vitamin D status and the risk of multiple sclerosis. Vitamin D affects the regulation of T-lymphocytes, and T-lymphocytes, in turn, play a role in the pathogenesis of multiple sclerosis [56].Conclusion. Thus, numerous studies indicate the diversity of the biological significance of vitamin D, its indisputable role in the development and functioning of the central nervous system of children. The task is to generalize the available data and form a unified concept for the prevention and treatment of vitamin D deficiency in the pediatric population.
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About the authors

Tatyana P. Kalashnikova

E.A. Vagner Perm State Medical University

Author for correspondence.
Email: tpkalashnikova@rambler.ru
ORCID iD: 0000-0002-3637-6902

MD, PhD, Professor, Department of Neurology and Medical Genetics

Russian Federation, Perm

A. V. Popovskaya

E.A. Vagner Perm State Medical University

Email: tpkalashnikova@rambler.ru

forth-year student, Pediatric Faculty

Russian Federation, Perm

A. V. Minasanova

E.A. Vagner Perm State Medical University

Email: tpkalashnikova@rambler.ru

forth-year student, Pediatric Faculty

Russian Federation, Perm

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