The Putative Role of 1,25(OH)2D3 in the Association of Milk Consumption and
Parkinson’s Disease


Florian Langa    Ke Maa,b    Christina B. Leibrockc    Madhuri S. Salkerd    Yogesh Singhe


aDepartment of Physiology, Eberhard-Karls-University of Tübingen, Tübingen, Germany, bDepartment of Pharmacology, Experimental Therapy & Toxicology, Eberhard-Karls-University of Tübingen, Tübingen, Germany, cFresenius Kabi Deutschland GmbH, Bad Homburg, Germany, dResearch Institute of Women’s Health, University Hospital, Eberhard-Karls-University of Tübingen, Tübingen, Germany, eInstitute of Medical Genetics and Applied Genomics, NGS Competence Centre Tübingen (NCCT), Eberhard-Karls-University of Tübingen, Tübingen, Germany





Key Words

Dairy • 1,25(OH)2D3 • Oxidative stress • Neuroinflammation • Neurotrophins • Neuroprotection • Substantia nigra



The consumption of dairy products, particularly of low fat milk, has been shown to be associated with the occurrence of Parkinson’s disease. This association does not necessarily reflect a pathophysiological role of milk intake in the development of Parkinson’s disease. Nevertheless, the present review discusses a potential mechanism possibly mediating an effect of milk consumption on Parkinson’s disease. The case is made that milk is tailored in part to support bone mineralization of the suckling offspring and is thus rich in calcium and phosphate. Milk intake is thus expected to enhance intestinal calcium phosphate uptake. As binding to fatty acids impedes Ca2+ absorption, low fat milk is particularly effective. Calcium and phosphate uptake inhibit the formation of 1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol), the active form of vitamin D. Calcium inhibits 1,25(OH)2D3 production in part by suppressing the release of parathyroid hormone, a powerful stimulator of 1,25(OH)2D3 formation. Phosphate excess stimulates the release of fibroblast growth factor FGF23, which suppresses 1,25(OH)2D3 formation, an effect requiring Klotho. 1,25(OH)2D3 is a main regulator of mineral metabolism, but has powerful effects apparently unrelated to mineral metabolism, including suppression of inflammation and influence of multiple brain functions. In mice, lack of 1,25(OH)2D3 and excessive 1,25(OH)2D3 formation have profound effects on several types of behavior, such as explorative behavior, anxiety, grooming and social behavior. 1,25(OH)2D3 is produced in human brain and influences the function of various structures including substantia nigra. In neurons 1,25(OH)2D3 suppresses oxidative stress, inhibits inflammation and stimulates neurotrophin formation thus providing neuroprotection. As a result, 1,25(OH)2D3 is considered to favorably influence the clinical course of Parkinson’s disease. In conclusion, consumption of milk could in theory accelerate the downhill course of neuronal function in Parkinson’s disease. However, substantial additional experimentation is required to define the putative causal role of 1,25(OH)2D3 in the pathophysiology of Parkinson’s disease and its sensitivity to milk consumption.





Several studies uncovered an association of milk consumption and risk of Parkinson’s disease [1-8]. According to analysis of 2 large prospective cohort studies (n = 80,736 and 48,610, resp., follow up 26 and 24 years, resp.), consumption of skim and low fat milk was more influential than consumption of full fat milk [2]. The association does not necessarily reflect a causal role of milk consumption in the pathogenesis of Parkinson’s disease. Instead, consequences of Parkinson’s disease may impact on milk consumption. For instance, early loss of smell (anosmia) during the course of Parkinson’s disease [9] may in theory influence eating habits of the patient. Moreover, a common cause could in theory account for Parkinson’s disease and alterations of eating habits. Nevertheless, the observation of an association may reflect a causal relationship and deserves considerations about potential underlying mechanisms. The present review discusses the possibility that milk consumption triggers Parkinson’s disease by interference with the formation of calcitriol or 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) [10-12], which not only stimulates intestinal and renal Ca2+ and phosphate transport [10, 12], but has a multitude of effects unrelated to mineral metabolism including neuroprotection [13].


Milk consumption enhances intestinal calcium and phosphate uptake thus suppressing formation of 1,25(OH)2D3, a major regulator of mineral metabolism


In order to support bone mineralization of the suckling offspring, milk is rich in calcium phosphate [8]. Thus, milk consumption is expected to enhance intestinal uptake of calcium and phosphate.

Calcium and phosphate uptake impacts on formation of 1,25(OH)2D3, a powerful regulator of mineral metabolism [10-12]. 1,25(OH)2D3 is generated from vitamin D by hydroxylation to 25(OH)D3 [10, 11] followed by second hydroxylation to 1,25(OH)2D3 [10, 11, 13, 14]. The second hydroxylation is accomplished by a 25-hydroxyvitamin D3 -hydroxylase (1α-hydroxylase) [10, 11, 15], which is stimulated by calcium- and phosphate deficiency and parathyroid hormone [11-13, 16, 17]. Phosphate excess up-regulates fibroblast growth factor 23 (FGF23) [12, 18], which activates the co-receptor Klotho [19-21], a powerful inhibitor of 25-hydroxyvitamin D3 -hydroxylase [19]. Thus excess phosphate suppresses 1,25(OH)2D3 formation and thus further phosphate accumulation [18, 22, 23]. Hypercalcemia inhibits 1α-hydroxylase by suppressing release of parathyroid hormone [11-13, 16, 17]. The sensitivity of 25-hydroxyvitamin D3 -hydroxylase to calcium- and phosphate aims to adjust the 1,25(OH)2D3 formation exactly to the requirements of mineral metabolism. Further factors regulating 1,25(OH)2D3 formation include dehydration [24], volume depletion, mineralocorticoids, lithium, high fat diet, iron deficiency, CO-releasing molecule 2 (CORM-2) [25], leptin, catecholamines, tumor necrosis factor alpha (TNFα) and transforming growth factor beta 2 (TGFβ2) [13, 26-29]. To the extent that any of those regulators of 1,25(OH)2D3 formation is modified by milk consumption, it could contribute to the impact of milk consumption on Parkinson’s disease.   Moreover, in theory alterations of calcium and phosphate homeostasis may affect the development of Parkinson’s disease by mechanisms other than formation of 1,25(OH)2D3.



1,25(OH)2D3 participates in the regulation of multiple processes seemingly unrelated to mineral metabolism


1,25(OH)2D3 is not only a powerful regulator of mineral metabolism but participates in the regulation of diverse further functions [13], including inflammation and immune response [30-33], glucose metabolism [34], platelet activation [35], suicidal cell death [36-42], as well as neuronal function and survival [43-45]. Moreover, 25-hydroxyvitamin D3 -hydroxylase is expressed and thus 1,25(OH)2D3 produced in several extra-renal tissues including dendritic cells/macrophages, lymph nodes, thymus, skin (keratinocytes, hair follicles), placenta, lung, colon (epithelial cells and parasympathetic ganglia), stomach, pancreatic islets, adrenal medulla and brain [13, 46-54].

The 1,25(OH)2D3-binding vitamin D receptor (VDR) regulates the expression of as many as 500-1000 genes, which are involved in the regulation of a wide variety of cellular functions including transport, growth, differentiation and apoptosis [13, 55, 56].


1,25(OH)2D3 is generated in the brain and influences neuronal function and survival


Neurons, microglia and pericytes in several structures of the brain (including prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus, and substantia nigra [13, 48]) express 25-hydroxyvitamin D3 -hydroxylase and are thus capable to generate 1,25(OH)2D3 from 25(OH)D3 [46-48, 57]. Neurons are further able to produce 25(OH)D3 from cholecalciferol [57]. Similar to kidney, choroid plexus of the brain expresses klotho [19], which presumably participates in the regulation of cerebral 1,25(OH)2D3 formation.

Neurons, microglia and pericytes may further express the vitamin D receptor (VDR) and are thus sensitive to 1,25(OH)2D3 [58]. Upon binding of 1,25(OH)2D3 the VDR enters nuclei and modifies the expression of a wide variety of genes [58]. VDR-regulated genes detected in hippocampus include CCAAT/enhancer-binding protein beta (CEBPB), peripheral myelin protein 22 (PMP22), Plasma membrane calcium-transporting ATPase 3 (ATP2B3), Glutamate receptor AMPA 3 (GRIA3), Neurotrophic Receptor Tyrosine Kinase 2 (NTRK2), DNA Methyltransferase 3 Alpha (DNMT3A), Tenascin R (TNR), and glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) [13, 59], genes implicated in the pathophysiology of Parkinson’s disease [60-67]. As 1,25(OH)2D3 is a powerful regulator of neuronal gene expression, it has been considered a neurosteroid [57].

1,25(OH)2D3 confers neuroprotection, an effect in part due to counteraction of oxidation, inflammation, and vascular injury, as well as up-regulation of neurotrophins, improvement of metabolism and favorable influence on cardiovascular function [13, 44, 68].

1,25(OH)2D3 stimulates differentiation of dopaminergic neurons [68-70] leading to reduced expression of Neurogenin-2 (NEUROG2), a marker of immature dopaminergic neurons [69]. 1,25(OH)2D3 up-regulates N-cadherin [70], tyrosine hydroxylase, catechol-O-Methyltransferase (COMT) [69, 70], dopamine synthesis and dopamine metabolism [68-70]. 1,25(OH)2D3 supports the survival of dopaminergic neurons by up-regulation of glial cell-derived neurotrophic factor (GDNF) and its receptors [71, 72].

In neuroblastoma cells, 1,25(OH)2D3 has been shown to decrease cell proliferation and to stimulate differentiation [73]. 1,25(OH)2D3 has further been shown to up-regulate nerve growth factor (NGF) expression [73], TGFβ2 expression [74] and protein kinase C (PKC) activity [74]. 1,25(OH)2D3, has been shown to down-regulate myc expression [75].

1,25(OH)2D3 stimulates expression of several neurotrophic and neuroprotective factors including neurotrophin 3 (NT-3) [76], brain-derived neurotrophic factor (BDNF) [76], glial cell-derived neurotrophic factor (GDNF) [76], ciliary neurotrophic factor (CNTF) [76], and neuroprotective cytokine IL-34 [77]. The neurotrophic factors support neural cell survival and differentiation [76]. 1,25(OH)2D3 thus supports growth, survival, proliferation and differentiation of neurons and of neural stem cells [68]. Vitamin D deficiency may compromise neuronal development, dopamine transport and metabolism [78].

1,25(OH)2D3 may counteract inflammation, demyelination and neuron loss [79, 80]. 1,25(OH)2D3 decreases nitrite formation and oxidative stress [81]. Conversely, 1,25(OH)2D3 may support formation of neural stem cells, oligodendrocyte precursor cells and oligodendrocytes [79]. 1,25(OH)2D3 may down-regulate pro-inflammatory mediators, such as interferon gamma (IFN-γ), granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein 2 (MIP-2) as well as interleukins 6 (IL-6) and 17A (IL-17A). Conversely, 1,25(OH)2D3 may up-regulate anti-inflammatory interleukins 4 (IL-4) and 10 (IL-10) [79, 81]. 1,25(OH)2D3 suppresses activity of T-cells [82], 1,25(OH)2D3 is a powerful suppressor of cyclooxygenase (COX) [83, 84], an inflammatory enzyme apparently involved in the pathophysiology of Parkinson’s disease [85].

Further mechanisms invoked in the cerebral effects of 1,25(OH)2D3 include up-regulation of Beclin1 and of B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio [80], Amyloid beta (Aβ) – scavenger receptor low density lipoprotein receptor related protein (LRP-1) [86], sphingosine kinase activity and thus the sphingosine-1-phosphate (S1P)/ceramide (Cer) ratio [72], as well as downregulation of lipid modified form of microtubule-associated proteins 1A/1B light chain 3B (LC3-II) [80], p38 mitogen-activated protein kinases (p38-MAPK), extracellular signal-regulated kinases (ERK), and c-Jun N-terminal kinase (JNK) activation [81], the ratio p38-MAPK/activating transcription factor 4 (ATF4) [72] and endoplasmatic reticulum (ER) stress damage [72].

1,25(OH)2D3 may further be effective by cytosolic Ca2+ activity in neurons and/or glial cells [58, 87-89]. 1,25(OH)2D3 has been shown to up-regulate Ca2+ -binding protein in the pineal gland [90]. 1,25(OH)2D3 may further be effective by suppressing glucocorticoid sensitivity of the brain [91].

1,25(OH)2D3 influences behavior and mood: In mice, excessive 1,25(OH)2D3 leads to an amazing increase of exploratory behavior and to a shortening of floating in the forced swimming test which reflects decreased depression [92]. Vitamin D deficiency downregulates explorative behavior and leads to anxiety, aberrant grooming, submissive social behavior, social neglect and maternal cannibalism [93-95]. Vitamin D deficiency before birth impacts on murine self-grooming [96]. Vitamin D receptor (VDR) deficiency exerts similar effects as Vitamin D deficiency [94, 97-102]. 1,25(OH)2D3 similarly affects human behavior [44, 45], emotions [103] and anxiety [103]. Vitamin D deficiency may trigger [104, 105] and vitamin D supplementation may counteract [106-108] depression. Vitamin D deficiency fosters the development of bipolar disorder and schizophrenia [103, 109-111]. 1,25(OH)2D3 may influence extraversion [112], social phobia, cluster C personality disorders and suicide risk [111, 113]. Seasonal variations of sun exposure may alter cutaneous vitamin D formation and thus trigger seasonal affective disorders [106-108, 114]. Vitamin D deficiency during brain development may foster [115] and vitamin D supplementation may counteract [110] development of schizophrenia. Vitamin D supplementation may further reduce ± 3,4-methylenedioxymethamphetamine (ecstacy) toxicity [59]. Human behavior [116, 117] as well as age-related decline of cognitive function and appearance of depression [116] are affected by certain VDR gene variants.


Table 1. 1,25(OH)2D3-regulated molecules and mechanisms suggested to participate in the pathophysiology of Parkinson´s disease (for references see text)





At least in theory, skim milk may accelerate development and progression of Parkinson’s disease by suppression of 1,25(OH)2D3 formation. 1,25(OH)2D3 is generated in the brain and influences neuronal function and survival by a variety of mechanisms. 1,25(OH)2D3 is partially effective by counteracting oxidative stress, inflammation, and neuronal cell death. 1,25(OH)2D3 downregulates inflammatory mediators and up-regulates neuroprotective neurotrophins. As a result, 1,25(OH)2D3 protects against Parkinson’s disease. At least in theory, disease onset and clinical course of the disease could be favorably influenced by avoidance of skim milk and/or by treatment of affected patients with 1,25(OH)2D3 or synthetic VDR-agonists, such as paricalcitol, maxacalcitol, doxercalciferol, and falecalcitriol [118-122]. The evidence presently available is however suggestive, but not conclusive and additional experimentation is warranted further dissecting the pathophysiological role of 1,25(OH)2D3 in onset and course of Parkinson’s disease. Moreover, further clinical studies are required to define the impact of milk consumption, dietary phosphate, mineral metabolism, 1,25(OH)2D3 and/or synthetic VDR-agonists on the clinical course of Parkinson’s disease.



Disclosure Statement


The authors have no conflicts of interests.





1 Olsson E, Byberg L, Hoijer J, Kilander L, Larsson SC: Milk and Fermented Milk Intake and Parkinson's Disease: Cohort Study. Nutrients 2020;12:2763.


2 Hughes KC, Gao X, Kim IY, Wang M, Weisskopf MG, Schwarzschild MA, Ascherio A: Intake of dairy foods and risk of Parkinson disease. Neurology 2017;89:46-52.


3 Park M, Ross GW, Petrovitch H, White LR, Masaki KH, Nelson JS, Tanner CM, Curb JD, Blanchette PL, Abbott RD: Consumption of milk and calcium in midlife and the future risk of Parkinson disease. Neurology 2005;64:1047-1051.


4 Chen H, O'Reilly E, McCullough ML, Rodriguez C, Schwarzschild MA, Calle EE, Thun MJ, Ascherio A: Consumption of dairy products and risk of Parkinson's disease. Am J Epidemiol 2007;165:998-1006.


5 Saaksjarvi K, Knekt P, Lundqvist A, Mannisto S, Heliovaara M, Rissanen H, Jarvinen R: A cohort study on diet and the risk of Parkinson's disease: the role of food groups and diet quality. Br J Nutr 2013;109:329-337.


6 Kyrozis A, Ghika A, Stathopoulos P, Vassilopoulos D, Trichopoulos D, Trichopoulou A: Dietary and lifestyle variables in relation to incidence of Parkinson's disease in Greece. Eur J Epidemiol 2013;28:67-77.


7 Ascherio A, Schwarzschild MA: The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol 2016;15:1257-1272.


8 Gaucheron F: The minerals of milk. Reprod Nutr Dev 2005;45:473-483.


9 Shah M, Deeb J, Fernando M, Noyce A, Visentin E, Findley LJ, Hawkes CH: Abnormality of taste and smell in Parkinson's disease. Parkinsonism Relat Disord 2009;15:232-237.


10 Basit S: Vitamin D in health and disease: a literature review. Br J Biomed Sci 2013;70:161-172.


11 Liberman UA: Disorders in vitamin D action; in Feingold KR, Anawalt B, Boyce A, et al. (eds).: Endotext [Internet],, Inc., 2014.


12 Olmos-Ortiz A, Avila E, Durand-Carbajal M, Diaz L: Regulation of calcitriol biosynthesis and activity: focus on gestational vitamin D deficiency and adverse pregnancy outcomes. Nutrients 2015;7:443-480.


13 Lang F, Ma K, Leibrock CB: 1,25(OH)2D3 in Brain Function and Neuropsychiatric Disease. Neurosignals 2019;27:40-49.


14 Almilaji A, Honisch S, Liu G, Elvira B, Ajay SS, Hosseinzadeh Z, Ahmed M, Munoz C, Sopjani M, Lang F: Regulation of the Voltage Gated K+ Channel Kv1. 3 by Recombinant Human Klotho Protein. Kidney Blood Press Res 2014;39:609-622.


15 Zehnder D, Hewison M: The renal function of 25-hydroxyvitamin D3-1α-hydroxylase. Mol Cell Endocrinol 1999;151:213-220.


16 Latus J, Lehmann R, Roesel M, Fritz P, Braun N, Ulmer C, Steurer W, Biegger D, Ott G, Dippon J: Analysis of α-Klotho, fibroblast growth factor-, vitamin-D and calcium-sensing receptor in 70 patients with secondary hyperparathyroidism. Kidney Blood Press Res 2013;37:84-94.


17 Rodriguez M, Nemeth E, Martin D: The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism. Am J Physiol Renal Physiol 2005;288:F253-264.


18 Bergwitz C, Juppner H: Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 2010;61:91-104.


19 Kuro-o M: Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nat Rev Nephrol 2013;9:650-660.


20 Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E: Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45-51.


21 Torres PU, Prie D, Molina-Bletry V, Beck L, Silve C, Friedlander G: Klotho: an antiaging protein involved in mineral and vitamin D metabolism. Kidney Int 2007;71:730-737.


22 Borst O, Schaub M, Walker B, Sauter M, Muenzer P, Gramlich M, Mueller K, Geisler T, Lang F, Klingel K, Kandolf R, Bigalke B, Gawaz M, Zuern CS: CXCL16 is a novel diagnostic marker and predictor of mortality in inflammatory cardiomyopathy and heart failure. Int J Cardiol 2014;176:896-903.


23 Hu MC, Shiizaki K, Kuro-o M, Moe OW: Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 2013;75:503-533.


24 Abed M, Feger M, Alzoubi K, Pakladok T, Frauenfeld L, Geiger C, Towhid ST, Lang F: Sensitization of erythrocytes to suicidal erythrocyte death following water deprivation. Kidney Blood Press Res 2013;37:567-578.


25 Feger M, Fajol A, Lebedeva A, Meissner A, Michael D, Voelkl J, Alesutan I, Schleicher E, Reichetzeder C, Hocher B: Effect of carbon monoxide donor CORM-2 on vitamin D3 metabolism. Kidney Blood Press Res 2013;37:496-505.


26 Fakhri H, Pathare G, Fajol A, Zhang B, Bock T, Kandolf R, Schleicher E, Biber J, Föller M, Lang UE: Regulation of mineral metabolism by lithium. Pflugers Arch 2014;466:467-475.


27 Zhang B, Yan J, Schmidt S, Salker MS, Alexander D, Föller M, Lang F: Lithium-sensitive store-operated Ca2+ entry in the regulation of FGF23 release. Neurosignals 2015;23:34-48.


28 Lang F, Leibrock C, Pandyra AA, Stournaras C, Wagner CA, Foller M: Phosphate Homeostasis, Inflammation and the Regulation of FGF-23. Kidney Blood Press Res 2018;43:1742-1748.


29 Bar L, Stournaras C, Lang F, Foller M: Regulation of fibroblast growth factor 23 (FGF23) in health and disease. FEBS Lett 2019;593:1879-1900.


30 Cantorna MT, Zhu Y, Froicu M, Wittke A: Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 2004;80:1717S-1720S.


31 Deluca HF, Cantorna MT: Vitamin D: its role and uses in immunology. FASEB J 2001;15:2579-2585.


32 Haroon M, Fitzgerald O: Vitamin D and its emerging role in immunopathology. Clin Rheumatol 2012;31:199-202.


33 Heine G, Niesner U, Chang HD, Steinmeyer A, Zugel U, Zuberbier T, Radbruch A, Worm M: 1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells. Eur J Immunol 2008;38:2210-2218.


34 Reis AF, Hauache OM, Velho G: Vitamin D endocrine system and the genetic susceptibility to diabetes, obesity and vascular disease. A review of evidence. Diabetes Metab 2005;31:318-325.


35 Borst O, Münzer P, Schmid E, Schmidt E-M, Russo A, Walker B, Yang W, Leibrock C, Szteyn K, Schmidt S: 1,25 (OH) 2 vitamin D3-dependent inhibition of platelet Ca2+ signaling and thrombus formation in klotho-deficient mice. FASEB J 2014;28:2108-2119.


36 Cakici C, Yigitbasi T, Ayla S, Karimkhani H, Bayramoglu F, Yigit P, Kilic E, Emekli N: Dose-dependent effects of vitamin 1,25(OH)2D3 on oxidative stress and apoptosis. J Basic Clin Physiol Pharmacol 2018;29:271-279.


37 Chiang KC, Yeh CN, Pang JH, Hsu JT, Yeh TS, Chen LW, Kuo SF, Hsieh PJ, Pan YC, Takano M, Chen TC, Feng TH, Kittaka A, Juang HH: 1alpha,25(OH)2D3 Analog, MART-10, Inhibits Neuroendocrine Tumor Cell Growth Through Induction of G0/G1 Cell-cycle Arrest and Apoptosis. Anticancer Res 2016;36:3307-3313.


38 Miao D, Scutt A: Recruitment, augmentation and apoptosis of rat osteoclasts in 1,25-(OH)2D3 response to short-term treatment with 1,25-dihydroxyvitamin D3 in vivo. BMC Musculoskelet Disord 2002;3:16.


39 Narvaez CJ, Welsh J: Differential effects of 1,25-dihydroxyvitamin D3 and tetradecanoylphorbol acetate on cell cycle and apoptosis of MCF-7 cells and a vitamin D3-resistant variant. Endocrinology 1997;138:4690-4698.


40 Simboli-Campbell M, Narvaez CJ, van Weelden K, Tenniswood M, Welsh J: Comparative effects of 1,25(OH)2D3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells. Breast Cancer Res Treat 1997;42:31-41.


41 Zhang CJ, Zhao D, Yin X, Zhang H, Ma L, Chen JP, Liu C, Yang XP: Effects of 1,25(OH)2D3 on proliferation and apoptosis of human glomerular mesangial cells. Am J Transl Res 2016;8:2659-2666.


42 Zhang J, Yao Z: Effect of 1,25(OH)2D3 on the growth and apoptosis of breast cancer cell line MCF-7. Chin Med J (Engl) 2000;113:124-128.


43 Cui X, Gooch H, Petty A, McGrath JJ, Eyles D: Vitamin D and the brain: Genomic and non-genomic actions. Mol Cell Endocrinol 2017;453:131-143.


44 Cherniack EP, Troen BR, Florez HJ, Roos BA, Levis S: Some new food for thought: the role of vitamin D in the mental health of older adults. Curr Psychiatry Rep 2009;11:12-19.


45 Schaller M, Murray DR: Pathogens, personality, and culture: Disease prevalence predicts worldwide variability in sociosexuality, extraversion, and openness to experience. J Pers Soc Psychol 2008;95:212-221.


46 Diesel B, Seifert M, Radermacher J, Fischer U, Tilgen W, Reichrath J, Meese E: Towards a complete picture of splice variants of the gene for 25-hydroxyvitamin D31alpha-hydroxylase in brain and skin cancer. J Steroid Biochem Mol Biol 2004;89-90:527-532.


47 El-Atifi M, Dreyfus M, Berger F, Wion D: Expression of CYP2R1 and VDR in human brain pericytes: the neurovascular vitamin D autocrine/paracrine model. Neuroreport 2015;26:245-248.


48 Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ: Distribution of the vitamin D receptor and 1α-hydroxylase in human brain. J Chem Neuroanat 2005;29:21-30.


49 Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, Kilby MD, Moss PA, Chakraverty R: Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 2003;170:5382-5390.


50 Hewison M, Kantorovich V, Liker HR, Van Herle AJ, Cohan P, Zehnder D, Adams JS: Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages. J Bone Miner Res 2003;18:579-582.


51 Radermacher J, Diesel B, Seifert M, Tilgen W, Reichrath J, Fischer U, Meese E: Expression analysis of CYP27B1 in tumor biopsies and cell cultures. Anticancer Res 2006;26:2683-2686.


52 Segersten U, Correa P, Hewison M, Hellman P, Dralle H, Carling T, Akerstrom G, Westin G: 25-hydroxyvitamin D(3)-1alpha-hydroxylase expression in normal and pathological parathyroid glands. J Clin Endocrinol Metab 2002;87:2967-2972.


53 Smolders J, Schuurman KG, van Strien ME, Melief J, Hendrickx D, Hol EM, van Eden C, Luchetti S, Huitinga I: Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis-affected brain tissue. J Neuropathol Exp Neurol 2013;72:91-105.


54 Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison M: Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 2001;86:888-894.


55 Reichrath J, Saternus R, Vogt T: Challenge and perspective: the relevance of ultraviolet (UV) radiation and the vitamin D endocrine system (VDES) for psoriasis and other inflammatory skin diseases. Photochem Photobiol Sci 2017;16:433-444.


56 Reichrath J, Zouboulis CC, Vogt T, Holick MF: Targeting the vitamin D endocrine system (VDES) for the management of inflammatory and malignant skin diseases: An historical view and outlook. Rev Endocr Metab Disord 2016;17:405-417.


57 Landel V, Stephan D, Cui X, Eyles D, Feron F: Differential expression of vitamin D-associated enzymes and receptors in brain cell subtypes. J Steroid Biochem Mol Biol 2018;177:129-134.


58 Stumpf WE, Sar M, Clark SA, DeLuca HF: Brain target sites for 1,25-dihydroxyvitamin D3. Science 1982;215:1403-1405.


59 Petschner P, Balogh N, Adori C, Tamasi V, Kumar S, Juhasz G, Bagdy G: Downregulation of the Vitamin D Receptor Regulated Gene Set in the Hippocampus After MDMA Treatment. Front Pharmacol 2018;9:1373.


60 Brenner S, Wersinger C, Gasser T: Transcriptional regulation of the alpha-synuclein gene in human brain tissue. Neurosci Lett 2015;599:140-145.


61 Duke DC, Moran LB, Pearce RK, Graeber MB: The medial and lateral substantia nigra in Parkinson's disease: mRNA profiles associated with higher brain tissue vulnerability. Neurogenetics 2007;8:83-94.


62 Zaidi A, Adewale M, McLean L, Ramlow P: The plasma membrane calcium pumps-The old and the new. Neurosci Lett 2018;663:12-17.


63 Bereczki E, Branca RM, Francis PT, Pereira JB, Baek JH, Hortobagyi T, Winblad B, Ballard C, Lehtio J, Aarsland D: Synaptic markers of cognitive decline in neurodegenerative diseases: a proteomic approach. Brain 2018;141:582-595.


64 Farlow JL, Robak LA, Hetrick K, Bowling K, Boerwinkle E, Coban-Akdemir ZH, Gambin T, Gibbs RA, Gu S, Jain P, Jankovic J, Jhangiani S, Kaw K, Lai D, Lin H, Ling H, Liu Y, Lupski JR, Muzny D, Porter P, et al.: Whole-Exome Sequencing in Familial Parkinson Disease. JAMA Neurol 2016;73:68-75.


65 Ishii T, Warabi E, Mann GE: Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis. Free Radic Biol Med 2019;133:169-178.


66 Kantor B, Tagliafierro L, Gu J, Zamora ME, Ilich E, Grenier C, Huang ZY, Murphy S, Chiba-Falek O: Downregulation of SNCA Expression by Targeted Editing of DNA Methylation: A Potential Strategy for Precision Therapy in PD. Mol Ther 2018;26:2638-2649.


67 Simon DK, Wu C, Tilley BC, Lohmann K, Klein C, Payami H, Wills AM, Aminoff MJ, Bainbridge J, Dewey R, Hauser RA, Schaake S, Schneider JS, Sharma S, Singer C, Tanner CM, Truong D, Wei P, Wong PS, Yang T: Caffeine, creatine, GRIN2A and Parkinson's disease progression. J Neurol Sci 2017;375:355-359.


68 AlJohri R, AlOkail M, Haq SH: Neuroprotective role of vitamin D in primary neuronal cortical culture. eNeurologicalSci 2019;14:43-48.


69 Pertile RA, Cui X, Eyles DW: Vitamin D signaling and the differentiation of developing dopamine systems. Neuroscience 2016;333:193-203.


70 Cui X, Pertile R, Liu P, Eyles DW: Vitamin D regulates tyrosine hydroxylase expression: N-cadherin a possible mediator. Neuroscience 2015;304:90-100.


71 Pertile RAN, Cui X, Hammond L, Eyles DW: Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons. FASEB J 2018;32:819-828.


72 Pierucci F, Garcia-Gil M, Frati A, Bini F, Martinesi M, Vannini E, Mainardi M, Luzzati F, Peretto P, Caleo M, Meacci E: Vitamin D3 protects against Abeta peptide cytotoxicity in differentiated human neuroblastoma SH- SY5Y cells: A role for S1P1/p38MAPK/ATF4 axis. Neuropharmacology 2017;116:328-342.


73 Veenstra TD, Londowski JM, Windebank AJ, Brimijoin S, Kumar R: Effects of 1,25-dihydroxyvitamin D3 on growth of mouse neuroblastoma cells. Brain Res Dev Brain Res 1997;99:53-60.


74 Izquierdo MC, Perez-Gomez MV, Sanchez-Niño MD, Sanz AB, Ruiz-Andres O, Poveda J, Moreno JA, Egido J, Ortiz A: Klotho, phosphate and inflammation/ageing in chronic kidney disease. Nephrol Dial Transplant 2012;27:iv6-iv10.


75 Veenstra TD, Windebank AJ, Kumar R: 1,25-dihydroxyvitamin D3 regulates the expression of N-myc, c-myc, protein kinase C, and transforming growth factor-beta2 in neuroblastoma cells. Biochem Biophys Res Commun 1997;235:15-18.


76 Shirazi HA, Rasouli J, Ciric B, Rostami A, Zhang GX: 1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation. Exp Mol Pathol 2015;98:240-245.


77 Zhang D, Li M, Dong Y, Zhang X, Liu X, Chen Z, Zhu Y, Wang H, Liu X, Zhu J, Shen Y, Korner H, Ying S, Fang S, Shen Y: 1alpha,25-Dihydroxyvitamin D3 up-regulates IL-34 expression in SH-SY5Y neural cells. Innate Immun 2017;23:584-591.


78 Kesby JP, Cui X, O'Loan J, McGrath JJ, Burne TH, Eyles DW: Developmental vitamin D deficiency alters dopamine-mediated behaviors and dopamine transporter function in adult female rats. Psychopharmacology (Berl) 2010;208:159-168.


79 Shirazi HA, Rasouli J, Ciric B, Wei D, Rostami A, Zhang GX: 1,25-Dihydroxyvitamin D3 suppressed experimental autoimmune encephalomyelitis through both immunomodulation and oligodendrocyte maturation. Exp Mol Pathol 2017;102:515-521.


80 Zhen C, Feng X, Li Z, Wang Y, Li B, Li L, Quan M, Wang G, Guo L: Suppression of murine experimental autoimmune encephalomyelitis development by 1,25-dihydroxyvitamin D3 with autophagy modulation. J Neuroimmunol 2015;280:1-7.


81 Huang YN, Ho YJ, Lai CC, Chiu CT, Wang JY: 1,25-Dihydroxyvitamin D3 attenuates endotoxin-induced production of inflammatory mediators by inhibiting MAPK activation in primary cortical neuron-glia cultures. J Neuroinflammation 2015;12:147.


82 Lee WP, Willekens B, Cras P, Goossens H, Martinez-Caceres E, Berneman ZN, Cools N: Immunomodulatory Effects of 1,25-Dihydroxyvitamin D3 on Dendritic Cells Promote Induction of T Cell Hyporesponsiveness to Myelin-Derived Antigens. J Immunol Res 2016;2016:5392623.


83 Boyan BD, Sylvia VL, Dean DD, Pedrozo H, Del Toro F, Nemere I, Posner GH, Schwartz Z: 1,25-(OH)2D3 modulates growth plate chondrocytes via membrane receptor-mediated protein kinase C by a mechanism that involves changes in phospholipid metabolism and the action of arachidonic acid and PGE2. Steroids 1999;64:129-136.


84 Sun J, Zhong W, Gu Y, Groome LJ, Wang Y: 1,25(OH)2D3 suppresses COX-2 up-regulation and thromboxane production in placental trophoblast cells in response to hypoxic stimulation. Placenta 2014;35:143-145.


85 Teismann P, Ferger B: Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson's disease. Synapse 2001;39:167-174.<167::AID-SYN8>3.0.CO;2-U


86 Patel P, Shah J: Role of Vitamin D in Amyloid clearance via LRP-1 upregulation in Alzheimer's disease: A potential therapeutic target? J Chem Neuroanat 2017;85:36-42.


87 Khanal RC, Nemere I: Regulation of intestinal calcium transport. Annu Rev Nutr 2008;28:179-196.


88 Ramasamy I: Recent advances in physiological calcium homeostasis. Clin Chem Lab Med 2006;44:237-273.


89 Shumilina E, Xuan NT, Matzner N, Bhandaru M, Zemtsova IM, Lang F: Regulation of calcium signaling in dendritic cells by 1,25-dihydroxyvitamin D3. FASEB J 2010;24:1989-1996.


90 Celio M, Baier W, Schärer L, Gregersen H, De Viragh P, Norman A: Monoclonal antibodies directed against the calcium binding protein Calbindin D-28k. Cell calcium 1990;11:599-602.


91 Obradovic D, Gronemeyer H, Lutz B, Rein T: Cross‐talk of vitamin D and glucocorticoids in hippocampal cells. J Neurochem 2006;96:500-509.


92 Leibrock CB, Voelkl J, Kuro OM, Lang F, Lang UE: 1,25(OH)2D3 dependent overt hyperactivity phenotype in klotho-hypomorphic mice. Sci Rep 2016;6:24879.


93 Kalueff AV, Lou YR, Laaksi I, Tuohimaa P: Increased anxiety in mice lacking vitamin D receptor gene. Neuroreport 2004;15:1271-1274.


94 Kalueff AV, Lou YR, Laaksi I, Tuohimaa P: Abnormal behavioral organization of grooming in mice lacking the vitamin D receptor gene. J Neurogenet 2005;19:1-24.


95 Zou J, Minasyan A, Keisala T, Zhang Y, Wang JH, Lou YR, Kalueff A, Pyykkö I, Tuohimaa P: Progressive hearing loss in mice with a mutated vitamin D receptor gene. Audiol Neurootol 2008;13:219-230.


96 Burne TH, O'Loan J, Splatt K, Alexander S, McGrath JJ, Eyles DW: Developmental vitamin D (DVD) deficiency alters pup-retrieval but not isolation-induced pup ultrasonic vocalizations in the rat. Physiol Behav 2011;102:201-204.


97 Burne TH, Johnston AN, McGrath JJ, Mackay-Sim A: Swimming behaviour and post-swimming activity in Vitamin D receptor knockout mice. Brain Res Bull 2006;69:74-78.


98 Burne TH, McGrath JJ, Eyles DW, Mackay-Sim A: Behavioural characterization of vitamin D receptor knockout mice. Behav Brain Res 2005;157:299-308.


99 Kalueff A, Lou YR, Laaksi I, Tuohimaa P: Increased grooming behavior in mice lacking vitamin D receptors. Physiol Behav 2004;82:405-409.


100 Kalueff AV, Lou YR, Laaksi I, Tuohimaa P: Impaired motor performance in mice lacking neurosteroid vitamin D receptors. Brain Res Bull 2004;64:25-29.


101 Kalueff AV, Minasyan A, Keisala T, Kuuslahti M, Miettinen S, Tuohimaa P: Increased severity of chemically induced seizures in mice with partially deleted Vitamin D receptor gene. Neurosci Lett 2006;394:69-73.


102 Sakai S, Suzuki M, Tashiro Y, Tanaka K, Takeda S, Aizawa K, Hirata M, Yogo K, Endo K: Vitamin D receptor signaling enhances locomotive ability in mice. J Bone Miner Res2015;30:128-136.


103 Minasyan A, Keisala T, Lou YR, Kalueff AV, Tuohimaa P: Neophobia, sensory and cognitive functions, and hedonic responses in vitamin D receptor mutant mice. J Steroid Biochem Mol Biol 2007;104:274-280.


104 Hoogendijk WJ, Lips P, Dik MG, Deeg DJ, Beekman AT, Penninx BW: Depression is associated with decreased 25-hydroxyvitamin D and increased parathyroid hormone levels in older adults. Arch Gen Psychiatry 2008;65:508-512.


105 Wilkins CH, Sheline YI, Roe CM, Birge SJ, Morris JC: Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry 2006;14:1032-1040.


106 Bertone-Johnson ER: Vitamin D and the occurrence of depression: causal association or circumstantial evidence? Nutr Rev 2009;67:481-492.


107 Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K: Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects: randomized double blind trial. J Intern Med 2008;264:599-609.


108 Shipowick CD, Moore CB, Corbett C, Bindler R: Vitamin D and depressive symptoms in women during the winter: a pilot study. Appl Nurs Res 2009;22:221-225.


109 Glade MJ: Vitamin D: health panacea or false prophet? Nutrition 2013;29:37-41.


110 Hedelin M, Löf M, Olsson M, Lewander T, Nilsson B, Hultman CM, Weiderpass E: Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33 000 women from the general population. BMC Psychiatry 2010;10:38.


111 Jylhä P, Mantere O, Melartin T, Suominen K, Vuorilehto M, Arvilommi P, Leppämäki S, Valtonen H, Rytsälä H, Isometsä E: Differences in neuroticism and extraversion between patients with bipolar I or II and general population subjects or major depressive disorder patients. J Affect Disord 2010;125:42-52.


112 Ubbenhorst A, Striebich S, Lang F, Lang UE: Exploring the relationship between vitamin D and basic personality traits. Psychopharmacology 2011;215:733-737.


113 Voracek M: Big Five personality factors and suicide rates in the United States: A state-level analysis. Percept Mot Skills 2009;109:208-212.


114 Lansdowne AT, Provost SC: Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology 1998;135:319-323.


115 Herran A, Sierra-Biddle D, Cuesta MJ, Sandoya M, Vázquez-Barquero JL: Can personality traits help us explain disability in chronic schizophrenia? Psychiatry Clin Neurosci 2006;60:538-545.


116 Kuningas M, Mooijaart SP, Jolles J, Slagboom PE, Westendorp RG, van Heemst D: VDR gene variants associate with cognitive function and depressive symptoms in old age. Neurobiol Aging 2009;30:466-473.


117 Wrzosek M, Jakubczyk A, Wrzosek M, Kaleta B, Łukaszkiewicz J, Matsumoto H, Brower K, Nowicka G, Wojnar M: Association between Fok I vitamin D receptor gene (VDR) polymorphism and impulsivity in alcohol-dependent patients. Mol Biol Rep 2014;41:7223-7228.


118 Zhang Q, Li M, Zhang T, Chen J: Effect of Vitamin D Receptor Activators on Glomerular Filtration Rate: A Meta-Analysis and Systematic Review. PLoS One 2016;11:e0147347.


119 Biggar PH, Liangos O, Fey H, Brandenburg VM, Ketteler M: Vitamin D, chronic kidney disease and survival: a pluripotent hormone or just another bone drug? Pediatr Nephrol 2011;26:7-18.


120 Pavlovic D, Katicic D, Gulin T, Josipovic J: Vitamin d in the patients with chronic kidney disease: when, to whom and in which form. Mater Sociomed 2015;27:122-124.


121 Palmer SC, McGregor DO, Craig JC, Elder G, Macaskill P, Strippoli GF: Vitamin D compounds for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 2009:CD008175.


122 Brown AJ, Coyne DW: Vitamin D analogs: new therapeutic agents for secondary hyperparathyroidism. Treat Endocrinol 2002;1:313-327.