Vitamin D in Central Nervous System: Implications for Neurological Disorders

Abstract

Vitamin D, obtained from diet or synthesized internally as cholecalciferol and ergocalciferol, influences bodily functions through its most active metabolite and the vitamin D receptor. Recent research has uncovered multiple roles for vitamin D in the central nervous system, impacting neural development and maturation, regulating the dopaminergic system, and controlling the synthesis of neural growth factors. This review thoroughly examines these connections and investigates the consequences of vitamin D deficiency in neurological disorders, particularly neurodegenerative diseases. The potential benefits of vitamin D supplementation in alleviating symptoms of these diseases are evaluated alongside a discussion of the controversial findings from previous intervention studies. The importance of interpreting these results cautiously is emphasised. Furthermore, the article proposes that additional randomised and well-designed trials are essential for gaining a deeper understanding of the potential therapeutic advantages of vitamin D supplementation for neurological disorders. Ultimately, this review highlights the critical role of vitamin D in neurological well-being and highlights the need for further research to enhance our understanding of its function in the brain.

Keywords: brain; calcitriol; neurological disorders; vitamin D.

Figure 1

Sources of vitamin D₃ and pathways for calcitriol biosynthesis in the body. (A) The classical pathway involves the synthesis of VD₃ in the skin under the UVB radiation from the sun. This pathway starts with 7-dehydrocholesterol (7-HDC), a derivative of cholesterol, reacting to UV radiation to form cholecalciferol (VD₃) through an intermediate previtamin D₃ (Pre-VD₃). (B) The alternative pathway involves dietary intake of VD₃ or ergocalciferol (VD₂)-rich food such as fatty fish, eggs, or fortified milk products for VD₃ or plants and fungi for VD₂. Under normal circumstances, higher quantities are synthesised via classical pathways. VD₃ from both sources enters the circulation, binds to vitamin D binding protein (VDBP), and is transported to metabolic tissues. (C) The traditional synthetic pathway of 1$\alpha$,25-dihydroxyvitamin D₃ (calcitriol/1,25-VD₃), the most active metabolite of vitamin D, starts in the liver when VD₃ is hydroxylated at C25 by CYP2R1 (and in minority also CYP27A1) to yield 25-dihydroxyvitamin D₃ (calcidiol/25-VD₃), which is the major circulating storage form of vitamin D. (D) This 25-VD₃ is transported by VDBP to the kidney, where it is hydroxylated at position C1 by CYP27B1 to form 1$\alpha$,25-VD₃. The 1$\alpha$,25-VD₃ binds to its molecular target vitamin D receptor (VDR), which regulates the transcription of various target genes. (E) Vitamin D can also be transported directly to the brain as 25-VD₃ or 1$\alpha$,25-VD₃, where both can cross the blood–brain barrier. Additionally, 25-VD₃ can be converted to 1$\alpha$,25-VD₃ in the brain, since the enzymes involved in its synthesis are expressed in pericytes, glial cells, and neurons in addition to the liver and kidney. This suggest the possible of local synthesis of vitamin D metabolites in the brain and active signalling.

Figure 2

Schematic model illustrating the genomic and non-genomic effects of VD₃ in the CNS. (A) Genomic action of calcitriol: This model focuses on VD₃ target genes and signalling pathways that have been identified within the brain or neural cells (neurons, astrocytes, oligodendrocytes, or microglia). Genomic actions primarily occur within the nucleus. In this simplified model, calcitriol binds to the VDR/RXR complex, leading to the release of co-repressors and the recruitment of co-activators at vitamin D response elements (VDREs) located in regulatory regions, which promotes the expression of specific calcitriol target genes. The listed genes are those whose expression is influenced by VD₃ within the brain and for which functional VDREs have been identified on relevant regulatory regions. (B) Non-genomic action of VD₃: The non-genomic actions of ₃ are potentially mediated through the classical VDR, protein disulphide isomerase A3 (PDIA3), or both of these proteins. Upon calcitriol binding, the rapid activation of protein kinases such as CaMII, PKA, and PI3K occurs, which in turn facilitates the influx of Ca²⁺ ions via L-type voltage-gated calcium channels (L-VGCCs). Intracellular Ca²⁺ then triggers the activation of p38MAPK, further modulating downstream signalling pathways. Both the genomic and non-genomic actions of VD₃ are likely to have an impact on brain development, function, and maintenance. These mechanisms play a role in shaping the intricate processes within the CNS.

Figure 3

The connection between VD₃ and various neurological disorders is summarised in the figure. It highlights diseases in which molecular connections have been suggested between VD₃ signalling and gene regulatory or metabolic networks, such as the regulation of enzymes that facilitate the production of serotonin or melatonin. Additionally, a general neuroinflammation process has been proposed as a link to many neurological diseases, where VD₃ supplementation inhibits the expression of inflammatory cytokines and/or activates the expression of anti-inflammatory molecules. Throughout the figure, the following abbreviations have been used: glutathione (GSH), interleukin-1β (IL1B), tumour necrosis factor (TNF), L-type voltage-sensitive Ca²⁺ channel, glial cell-derived neurotrophic factor (GDNF), neurotrophin 3 (NTF3), nerve growth factor (NGF), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH1 and TPH2), N-methyl-D-aspartate receptor (NMDAR), inducible nitric oxide synthase (iNOS), prostaglandin-endoperoxide synthase 2 or cyclooxygenase-2 (COX2/PTGS2), insulin-degrading enzyme (IDE), low-density lipoprotein receptor-related protein 1 (LRP1), vitamin D receptor (VDR).

Figure 4

Overview of the effects of VD₃ on individual neurons and the whole brain.