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Abstract

Vitamin D is a steroid hormone produced photochemically in animal epidermis exposed to ultraviolet light (UVB). During the past 25 years, several studies have raised data showing that vitamin D exerts marked effects on brain physiology: (i) expression of the VDR receptor and 1α-hydroxylase by cerebral neurons, (ii) the epidemiological links between vitamin D status and central nervous system diseases, (iii) the association between mutations in genes implicated in vitamin D metabolism and cerebral disorders, (iv) the effects of vitamin D supplementation or depletion in animal models of neurodegenerative diseases, (v) the specific action of vitamin D on central nervous system cells, (vi) the discovery of vitamin D action on the immune system and inflammation. Here, we review all the data suggesting that vitamin D is an important cofactor in the occurrence and/or the evolution of neurodegenerative or psychiatric diseases.

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... In recent years, several scattered studies have reported cases of vitamin D deficiency and the vitamin's beneficial effect on a broad spectrum of acute or chronic diseases [4]. Central or peripheral neurological diseases can be involved [5,6], especially multiple sclerosis that has been widely studied [7,8]. It has been established that cerebral 1a-hydroxyase enables local transformation of cholecalciferol into calcitriol, its active form, suggesting a paracrine action at this level [9]. ...
... Millet et al. [7] reported that 1,25(OH)2D is bound ubiquitously in the embryonic brain, mainly in the neuroepithelium and in zones of proliferation. That in addition, VDR is largely expressed in the adult brain. ...
... The VDR gene itself is associated with some of them [5]. In addition, 1,25(OH)2D3 is found in cerebral spinal fluid and genes coding for its biosynthesis and its degradation are expressed in the brain [7,33]. Local synthesis of 1,25(OH)2D3 is accomplished by neurons and microglial cells expressing 1a-hydroxylase [9,13]. ...
Article
This review exposes recent advances on the role of vitamin D, cholecalciferol, a secosteroid, in the central nervous system. In humans, vitamin D arises from cutaneous transformation of 7-dehydrocholesterol under the effect of UVB exposure or from food intake. Vitamin D has an immunomodulatory role through its anti-inflammatory and anti-autoimmune actions. In the nervous system, vitamin D is involved in the regulation of calcium-mediated neuronal excitotoxicity, in the reduction of oxidative stress, and in the induction of synaptic structural proteins, neurotrophic factors and deficient neurotransmitters. Reduced exposure to sunlight and low food intake can lead to vitamin D deficiency. Increasing evidence highlights the impact of vitamin D deficiency as a favoring factor in various central or peripheral neurological diseases, especially multiple sclerosis and several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. Recently, several clinical trials on vitamin D supplementation stressed the role of vitamin D as a protective and/or prognostic factor in the onset and progress of such neurological conditions.
... Svakako je to bilo u fokusu i zbog geografske distribucije bolesti, koja je znatno učestalija u sjevernim dijelovima svijeta s manje sunčeve svjetlosti 19 . Dosadašnja su istraživanja pokazala povećan rizik za razvoj bolesti u slučaju nedostatka vitamina D 20 , pogotovo ukoliko je manjak prisutan u važnim fazama mijelinizacije tijekom adolescencije 21 . Nadalje, otkriveno je da kod bolesnika s kliničkim izoliranim sindromom (CIS), svojevrsnom mogućom pretečom multiple skle-roze, manjak vitamina D dovodi do većeg rizika progresije bolesti i prelaska u klinički potvrđenu multiplu sklerozu 22 . ...
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Vitamin D nužan je nutrijent potreban za homeostazu kalcija i zdravlje koštanog sustava, no sve se češće potvrđuje njegova uloga u neurološkim bolestima. U središnjem živčanom sustavu prisutni su svi čimbenici metabolizma vitamina D te je djelovanje moguće parakrinim i autokrinim putem. Vitamin D utječe na razine neurotrofnih čimbenika, regulaciju imunološke funkcije te na homeostazu središnjeg živčanog sustava. Manjak vitamina D i njegova nadoknada predmet je istraživanja većine neurodegenerativnih bolesti te je manjak povezan s povećanim rizikom nastanka bolesti. Dosadašnja su istraživanja nadoknađivanja vitamina D obećavajuća, no postoji nedostatak visokokvalitetnih studija za čvrste dokaze i smjernice.
... Vitamin D is present all over in the embryonic brain, and most predominantly in the neuroepithelium and in proliferation area of the embryonic brain. [22] Furthermore, the presence of the VDR in high levels in the developing brain substantiate the notion that vitamin D is involved in neurodevelopment. [23] Vitamin D is a nuclear steroid transcription regulator and employs transcriptional control over genes. ...
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Background: Vitamin D and its metabolites have a vital role to play in human health and diseases like cancer, Type 1 Diabetes, cardiovascular diseases, Osteoporosis, Osteomalacia, immune system, and the nervous system. In the nervous system vitamin D could influence the proliferation, differentiation of neurons also plays an important role in neuro-tropism, neurotransmission, and neuroplasticity. Further, in some cases, it was reported that vitamin D could provide neuroprotection by reduction of oxidative stress, induction of synaptic structural proteins, and regulation of calcium-mediated neuronal excitotoxicity, neurotrophic factors, and deficient neurotransmitters. Generally, there is hype and variations associated with the integrity of evidence on vitamins and their effect on health. Vitamin D deficiency continues to attract a renewed attention and adequate maintenance of vitamin D levels can prevent and reduce the risk of many diseases as the active form acts at the cell nucleus (gene upregulation) and cell membrane (rapid response) in over 30 tissues and organs targeting over 200 genes. Vitamin D tends to exert endocrine actions on the Kidneys, bones, and intestine. Paracrine role in tissues which are under cytokine control which are able to locally metabolize vitamin D to its active form to modulate immune functions, cell proliferation and differentiation and hence maintenance of adequate levels of vitamin D has a significant impact for optimal health. Establishing what constitutes vitamin D deficiency is currently replete with contradictory information. Objective: The present discourse aim is first to scrutinize and assess the literature on vitamin D function in the central nervous system (CNS). Another related aim of the present review is to highlight current data from countries with high exposure to the sun yet the people living in the region have been documented to have a deficit in vitamin D. Results and conclusions: In this review, we provide a Gulf centric view on vitamin D status among all age groups including public health impact and policy recommendations for the region. The role or status of vitamin D in the various disease states, the benefits of vitamin D and how to obtain an adequate daily amount.
... Concerning the pathophysiological mechanisms between vitamin D and psychiatric pathology, the role of vitamin D on cerebral structures has been shown to affect neuronal development, neuroplasticity through stimulation of axogenesis, neuro-protection by reducing oxidative stress and strengthening of the antioxidative immune system and, finally neurotransmission [42]. Vitamin D also has a general effect on inflammation and, therefore, potentially on cerebral inflammation [18,43,44]. ...
Article
Objectives: The main objective of the study was to assess 25-hydroxyvitamin D (25(OH)D) status in a psychiatric population in France according to psychiatric diagnoses. The secondary objective was to investigate a correlation between 25(OH)D and CRP. Methods: A retrospective study from February 1st, 2014 to January 31, 2016, was carried out in a French psychiatric hospital. Inpatients with a 25(OH)D measure were included. Variables including ethnic origin, BMI, psychiatric diagnoses, medical history and CRP were collected. Factors associated with 25(OH)D and CRP were studied in univariate and multivariate analyses, as was the correlation between 25(OH)D and CRP. Results: Among 604 patients included, 80.6% presented 25(OH)D deficiency of which 46.9% with 25(OH)D<50nmol/L. 25(OH)D varied with age, ethnic origin, BMI, season, CRP and medical history. It was associated with schizophrenia in univariate analysis but not in multivariate analyses considering age and BMI. CRP varied with age, BMI and medical conditions but not with psychiatric diagnoses. 25(OH)D was inversely correlated with CRP. Conclusion: This psychiatric population was significantly more deficient in 25(OH)D than the French population in general. 25(OH)D was inversely correlated with CRP as observed in the general population.
... Concerning the pathophysiological mechanisms between vitamin D and psychiatric pathology, the role of vitamin D on cerebral structures has been shown to affect neuronal development, neuroplasticity through stimulation of axogenesis, neuro-protection by reducing oxidative stress and strengthening of the antioxidative immune system and, finally neurotransmission [42]. Vitamin D also has a general effect on inflammation and, therefore, potentially on cerebral inflammation [18,43,44]. ...
Article
Objectives Although the literature suggest that alcohol misuse is common in medical students, few studies have investigated it in French medical residents. The present study aims at exploring the prevalence and associated characteristics of alcohol misuse in French medical residents Methods Medical residents working in one of 3 University Hospital in France (n=292) were invited to fill out an online survey using the mailing lists of the participating centers. Alcohol use was assessed with the 10-item self-report Alcohol Use Disorders Identification Test (AUDIT) (range 0-40) which provides scores for hazardous alcohol use, dependency symptoms and harmful alcohol use. Background variables were also collected. Results Mean participants’ age was 27.7 (SD=1.7) and 65.5% (n=190) of them were of female gender. Mean weekly hours of work at the hospital was 57.8 (SD=13.6) and mean number of validated rotations at the time of the assessment was 5.1 (SD=2.4). Mean AUDIT score was 4.5 (SD=3). Forty-four (15.1%) participants scored on the AUDIT above the cut-off (>7) for problem use and 51 of them (17.5%) reported binge drinking at least once a month. AUDIT total score was positively correlated with male gender (r=0.26) and cannabis use (r=0.40) while negatively associated with weekly hours of work (r=-0.12) and number of rotations validated (-0.13). In a regression analysis, only male gender predicted alcohol use. Conclusions Alcohol problem use is prevalent in French medical residents, is predicted by male gender and is strongly associated with cannabis use. Future research is needed to confirm these results.
Thesis
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Vitamin D plays an important role in bone metabolism and maintaining bone health. Recently, new evidence has revealed that vitamin D affects chronic diseases such as autoimmune diseases, cardiovascular diseases and certain cancers. The aim of this study was to evaluate the vitamin D status and the prevalence of vitamin D deficiency in an urban Korean population. This study included 8,976 participants (3,587 men and 5,389 women) aged 50 yr and older. Serum 25(OH)D level was measured by chemiluminescent microparticle immunoassay. The prevalence of vitamin D deficiency [25(OH)D < 20 ng/mL] was 59.7% and 86.5% in men and women, respectively. The prevalence of vitamin D deficiency increased significantly with age in men, but not in women and it decreased from April to July, more prominently in men than in women. These results suggest that sun exposure, intake of vitamin D supplement, and regular physical activities is recommended in an urban Koreans, especially in women.
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The objective of this paper is to estimate the association between multiple sclerosis (MS) and measures of sun exposure in specific age periods in Norway and Italy. A total of 1660 MS patients and 3050 controls from Italy and Norway who participated in a multinational case-control study (EnvIMS) reported sun habits during childhood and adolescence. A significant association between infrequent summer outdoor activity and increased MS risk was found in Norway and in Italy. The association was strongest between the ages of 16 and 18 years in Norway (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.30-2.59), and between birth and age 5 years in Italy (OR 1.56, 95% CI 1.16-2.10). In Italy a significant association was also found during winter (OR 1.42, 95% CI 1.03-1.97). Frequent sunscreen use between birth and the age of 6 years was associated with MS in Norway (OR 1.44, 95% CI 1.08-1.93) after adjusting for outdoor activity during the same period. Red hair (OR 1.67, 95% CI 1.06-2.63) and blonde hair (OR 1.36, 95% CI 1.09-1.70) were associated with MS after adjusting for outdoor activity and sunscreen use. Converging evidence from different measures underlines the beneficial effect of sun exposure on MS risk.
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Vitamin D deficiency is common in the elderly. Vitamin D deficiency may affect the mood of people who are deficient. We investigated vitamin D status in older primary care patients and explored associations with depression. A cross-sectional study was conducted and association analyses were performed. Primary care patients at a single academic medical center who were ≥60 years with serum total 25-hydroxyvitamin D (25[OH]D) levels were included in the analysis. The primary outcome was a diagnosis of depression. Frailty scores and medical comorbidity burden scores were collected as predictors. There were 1618 patients with a mean age of 73.8 years (±8.48). The majority (81%) had optimal (≥25 ng/mL) 25(OH)D range, but 17% met mild-moderate (10-24 ng/mL) and 3% met severe (<10 ng/mL) deficiencies. Those with severe deficiency were older (P < 0.001), more frail (P < 0.001), had higher medical comorbidity burden (P < 0.001), and more frequent depression (P = 0.013). The 694 (43%) with depression had a lower 25(OH)D than the nondepressed group (32.7 vs 35.0, P = 0.002). 25(OH)D was negatively correlated with age (r = -0.070, P = 0.005), frailty (r = -0.113, P < 0.001), and medical comorbidity burden (r = -0.101, P < 0.001). A 25(OH)D level was correlated with depression (odds ratio = 0.990 and 95% confidence interval [CI] = 0.983-0.998, P = 0.012). Those with severe vitamin D deficiency were twice as likely to have depression (odds ratio = 2.093 with 95% CI 1.092-4.011, P = 0.026). Vitamin D deficiency was present in a fifth of this older primary care population. Lower vitamin D levels were associated with depression. Those with severe deficiency were older and more likely had depression.
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Objective: No quantitative systematic review or meta-analysis of population-based epidemiological studies has been conducted to assess the association between serum 25-hydroxyvitamin D (25(OH)D) levels and the risk of depression. This study aimed to summarize the current evidence from cross-sectional and prospective cohort studies that have evaluated the association between 25(OH)D levels and the risk of depression. Methods: Relevant studies were identified by systematically searching the PubMed, EMBASE, Web of Science, and PsycINFO databases through April 2012. Cross-sectional and cohort studies that reported adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association of interest were included. The reported risk estimates for 25(OH)D categories were recalculated, employing a comprehensive trend estimation from summarized dose-response data. A pooled OR was calculated separately for cross-sectional and cohort studies using random-effects models. Results: In the meta-analysis, 25(OH)D levels were significantly inversely associated with depression in 5 of 11 case-control studies and 2 of 5 cohort studies. The pooled estimate of the adjusted OR of depression in 11 cross-sectional studies (n = 43,137) was 0.96 (95% CI = 0.94-0.99, I2 = 63%) for a 10 ng/ml increase in 25(OH)D levels. The 5 included cohort studies comprised 12,648 participants, primarily elderly individuals, whose serum 25(OH)D levels were measured, and 2,663 experienced depression events during follow-up. The pooled adjusted OR of depression was 0.92 (95% CI = 0.87-0.98, I2 = 50%) for a 10 ng/ml increase in 25(OH)D levels. Conclusions: Our results indicate an inverse association between serum 25(OH)D levels and the risk of depression. Further studies are warranted to establish whether this association is causal.
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It has been hypothesized that hypovitaminosis D is associated with depression but epidemiological evidence is limited. We investigated the association between depressive disorders and related clinical characteristics with blood concentrations of 25-hydroxyvitamin D [25(OH)D] in a large cohort. The sample consisted of participants (aged 18-65 years) from the Netherlands Study of Depression and Anxiety (NESDA) with a current (N=1102) or remitted (N=790) depressive disorder (major depressive disorder, dysthymia) defined according to DSM-IV criteria, and healthy controls (N=494). Serum levels of 25(OH)D measured and analyzed in multivariate analyses adjusting for sociodemographics, sunlight, urbanization, lifestyle and health. Of the sample, 33.6% had deficient or insufficient serum 25(OH)D (<50 nmol l(-1)). As compared with controls, lower 25(OH)D levels were found in participants with current depression (P=0.001, Cohen's d=0.21), particularly in those with the most severe symptoms (P=0.001, Cohen's d=0.44). In currently depressed persons, 25(OH)D was inversely associated with symptom severity (β=-0.19, s.e.=0.07, P=0.003) suggesting a dose-response gradient, and with risk (relative risk=0.90, 95% confidence interval=0.82-0.99, P=0.03) of having a depressive disorders at 2-year follow-up. This large cohort study indicates that low levels of 25(OH)D were associated to the presence and severity of depressive disorder suggesting that hypovitaminosis D may represent an underlying biological vulnerability for depression. Future studies should elucidate whether-the highly prevalent-hypovitaminosis D could be cost-effectively treated as part of preventive or treatment interventions for depression.Molecular Psychiatry advance online publication, 9 April 2013; doi:10.1038/mp.2013.36.
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The contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis (MS) is reviewed. Among the multiple recently discovered actions of vitamin D, an immunomodulatory role has been documented in experimental autoimmune encephalomyelitis and in humans. This action in the peripheral immune system is currently the main known mechanism through which vitamin D might influence MS, but other types of actions could be involved within the central nervous system. Furthermore, vitamin D insufficiency is widespread in temperate countries and in patients with MS at the earliest stages of the disease, suggesting that the deleterious effects related to vitamin D insufficiency may be exerted in these patients. In fact, many genetic and environmental risk factors appear to interact and contribute to MS. In genetics, several human leukocyte antigen (HLA) alleles (more particularly HLA-DRB1*1501) could favour the disease whereas some others could be protective. Some of the genes involved in vitamin D metabolism (e.g. CYP27B1) also play a significant role. Furthermore, three environmental risk factors have been identified: past Epstein-Barr virus infection, vitamin D insufficiency and cigarette smoking. Interactions between genetic and environmental risk or protective factors may occur during the mother's pregnancy and could continue during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life. Furthermore, some clinical findings already strongly suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS, although the results of adequately powered randomized clinical trials using vitamin D supplementation have not yet been reported. While awaiting these incontrovertible results, which might be long in coming, patients with MS who are currently in vitamin D insufficiency should be supplemented, at least for their general health status, using moderate doses of the vitamin.
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1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) suppresses autoimmunity and inflammation; however, the mechanism of its action has not been fully understood. We sought in this study to determine whether the anti-immune/anti-inflammatory action of 1,25(OH)2D3 is in part mediated through an interplay between 1,25(OH)2D3 and toll-like receptor (TLR)7/8 signaling. 1,25(OH)2D3 treatment prior to and/or following experimental autoimmune encephalomyelitis (EAE) induction effectively reduced inflammatory cytokine expression in the spinal cord and ameliorated EAE. These effects were accompanied with a reduction in expression of several TLRs with the most profound effect observed for TLR8. The expression of TLR8 adaptor protein MyD88 was also significantly reduced by 1,25(OH)2D3. To determine the molecular mechanism by which 1,25(OH)2D3 suppresses EAE induction of TLR8 and inflammatory cytokine expression, we evaluated whether 1,25(OH)2D3 can directly inhibit TLR8 signaling and the resulting inflammatory responses in human THP-1 monocytes. 1,25(OH)2D3 treatment not only significantly reduced TLR8 expression but also the expression or activity of MyD88, IRF-4, IRF-7 and NF-kB in monocytes challenged with TLR8 ligands. TLR8 promoter-luciferase reporter assays indicated that 1,25(OH)2D3 decreases TLR8 mRNA level in part via inhibiting TLR8 gene transcription activity. As a result of inhibition on TLR8 signaling cascade at various stages, 1,25(OH)2D3 significantly diminished the TLR8 target gene expression (TNF-α and IL-1β). In summary, our novel findings suggest that TLR8 is a new target of 1,25(OH)2D3 and may mediate the anti-inflammatory action of 1,25(OH)2D3. Our findings also point to a destructive role of TLR8 in EAE and shed lights on pathogenesis of multiple sclerosis.
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Seasonal or chronic vitamin D deficiency and/or insufficiency is highly prevalent in the human population. Receptors for 1,25-dihydroxyvitamin D3, the hormonal metabolite of vitamin D, are found throughout the brain. To provide further information on the role of this hormone on brain function, we analyzed the transcriptomic profiles of mixed neuron-glial cell cultures in response to 1,25-dihydroxyvitamin D3. 1,25-dihydroxyvitamin D3 treatment increases the mRNA levels of 27 genes by at least 1.9 fold. Among them, 17 genes were related to neurodegenerative and psychiatric diseases, or brain morphogenesis. Notably, 10 of these genes encode proteins potentially limiting the progression of Alzheimer's disease. These data provide support for a role of 1,25-dihydroxyvitamin D3 in brain disease prevention. The possible consequences of circannual or chronic vitamin D insufficiencies on a tissue with a low regenerative potential such as the brain should be considered.
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Despite the fact that sunlight-dependent skin synthesis is the major mechanism for vitamin D synthesis in vivo, vitamin D-deficiency rickets continues to occur in exclusively breastfed infants in Greece. We present such a case in a 5-month-old infant who presented with afebrile seizures and whose mother was underexposed to sunlight due to veiling for religious reasons. Additionally, we briefly but thoroughly review the relevant medical literature. A high index of suspicion is required for nutritional rickets, when seizures occur in exclusively breastfed infants whose mothers have inadequate exposure to sunlight.
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Vitamin D deficiency is now recognized as an epidemic in the United States. The major source of vitamin D for both children and adults is from sensible sun exposure. In the absence of sun exposure 1000 IU of cholecalciferol is required daily for both children and adults. Vitamin D deficiency causes poor mineralization of the Collagen matrix in young children's bones leading to growth retardation and bone deformities known as rickets. In adults, vitamin D deficiency induces secondary hyperparathyroidism, which causes a loss of matrix and minerals, thus increasing the risk of osteoporosis and fractures. In addition, the poor mineralization of newly laid down bone matrix in adult bone results in the painful bone disease of osteomalacia. Vitamin D deficiency causes muscle weakness, increasing the risk of falling and fractures. Vitamin D deficiency also has other serious consequences on overall health and well-being. There is mounting scientific evidence that implicates vitamin D deficiency with an increased risk of type I diabetes, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and many common deadly cancers. Vigilance of one's vitamin D status by the yearly measurement of 25-hydroxyvitamin D should be part of an annual physical examination.
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Receptors for vitamin D hormone (VDR) and the calcium binding protein, calbindin-28k, have been localized in many tissues, including brain. In brain, VDR and calbindin-28k were reported to colocalize in hippocampal CA1 cells. We have shown that mRNA pool size for calbindin-28k was reduced, on average, by 35% in Alzheimer hippocampal CA1 cells, as compared to Huntington control (manuscript in preparation). In the present study, in situ hybridization with tritiated antisense RNA probes was used to examine VDR expression in paired Alzheimer and Huntington brain tissue. Message levels for VDR were reduced, on average, by 34% and 31%, respectively, in Alzheimer hippocampal CA1 and CA2 pyramidal cells, as compared to Huntington control. However, VDR message levels were not significantly different from control in Alzheimer temporal cortex or cerebellum. There was no correlation between VDR message levels and brain weight, autopsy interval, patient age or the extent of neurofibrillary degeneration. Instead, VDR mRNA pool size in hippocampal CA1 cells correlated significantly with calbindin-28k message levels (r = 0.52, P < 0.001). Decreased message levels for VDR and calbindin-28k in these cells were due to an increased percentage of cells expressing lower message levels for these proteins. These results show that in Alzheimer hippocampal CA1 cells, VDR mRNA pool size is downregulated and that this downregulation may play a role in the reduction of calbindin-28k expression.
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Background: Although Vitamin D is best known as a calcium homeostasis modulator, it also has immune modulating potential, as shown by its protective effect against MS development, supported by reduced disease risk associated with sun exposure and Vitamin D supplement use. Elevated Vitamin D blood levels have also been associated with lower risk of MS. Objective: To study the immunomodulatory effects of Vitamin D in MS. Methods: Serum 25(OH)D3 and 1,25(OH)2D3 levels were measured using ELISA in 58 relapsing remitting MS (RRMS) patients during remission, 34 RRMS patients during relapses, 40 primary progressive MS (PPMS) subjects and 60 healthy controls. Cell proliferation was measured using [3H]-thymidine incorporation assays. Vitamin D receptor (VDR), α1-hydroxylase, and indoleamine 2,3-dioxygenase (IDO) expression was measured by RT-PCR, while cytokine production was evaluated using ELISPOT. CD4+CD25+ regulatory T cells were studied using flow cytometry. Results: 25(OH)D3 and 1,25(OH) 2D3 levels were significantly lower in RRMS patients than in controls, more during relapses than remissions. By contrast, PPMS patients showed similar levels to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specific T cells was inhibited by 1,25(OH)2D 3. Activated Vitamin D also enhanced IL-10 producing cell development, and reduced IL-6, and IL-17 secreting cell numbers. 1,25(OH) 2D3 induced VDR expression in both activated and resting cells. Interestingly, T cells metabolized 25(OH)D3 into biologically active 1,25(OH)2D3, since they constitutively express α1-hydroxylase. Finally, 1,25(OH)2D3 also increased expression and biological activity of IDO, triggering significant increase in the number of CD4+CD25+ regulatory T cells. Conclusions: 1,25(OH) 2D3 plays an important role in T cell homeostasis during RRMS. Correction of its deficiency may prove useful in the treatment of the disease.
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At least 80% of the whole Polish population, including prepubertal children and adolescents, adults and seniors, are vitamin D deficient, defined as 25(OH)D < 50 nmol/L. 83% of Polish newborns start their lives at the state of vitamin D deficiency because 78% of their mothers are also deficient. It was observed that treating patient vitamin D deficiency to vitamin D status serum 25(OH)D) 75-100 nmol/L increased effectiveness of therapies in infectious diseases (chronic hepatitis C, tuberculosis), osteoporosis, multiple sclerosis, epilepsy, Chronic Kidney Diseases and atopic dermatitis. . For these reasons doctors should take special attension to vitamin D status in patients suffering for these diseases properly implementing recent vitamin D recommendation.
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Multiple sclerosis is primarily an inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to damage of myelin and axons. Initially, inflammation is transient and remyelination occurs but is not durable. Hence, the early course of disease is characterised by episodes of neurological dysfunction that usually recover. However, over time the pathological changes become dominated by widespread microglial activation associated with extensive and chronic neurodegeneration, the clinical correlate of which is progressive accumulation of disability. Paraclinical investigations show abnormalities that indicate the distribution of inflammatory lesions and axonal loss (MRI); interference of conduction in previously myelinated pathways (evoked electrophysiological potentials); and intrathecal synthesis of oligoclonal antibody (examination by lumbar puncture of the cerebrospinal fluid). Multiple sclerosis is triggered by environmental factors in individuals with complex genetic-risk profiles. Licensed disease modifying agents reduce the frequency of new episodes but do not reverse fixed deficits and have questionable effects on the long-term accumulation of disability and disease progression. We anticipate that future studies in multiple sclerosis will provide a new taxonomy on the basis of mechanisms rather than clinical empiricism, and so inform strategies for improved treatment at all stages of the disease.
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Scientists have worked for over a century to uncover the basis of Alzheimer's disease (AD) with the ultimate goal of discovering a treatment. However, none of the approaches utilized have defined the exact cause of the disease or an ultimate treatment for AD. In this review, we aim to define the role of vitamin D in AD from a novel and fundamental perspective and attempt to answer the following question: Why should we seriously consider "simple" vitamin D as a "fundamental factor" in AD? To answer this question, we explain the protective effects of vitamin D in the central nervous system and how the action of vitamin D and AD-type pathology overlap. Furthermore, we suggest that the role of vitamin D in AD includes not only vitamin D deficiency and vitamin D-related genes but also the disruption of vitamin D metabolism and action. This suggestion is supported by evidence that the disruption of vitamin D pathways mimic amyloid pathology. We define the term "inefficient utilization of vitamin D" as any alteration in vitamin D-related genes, including receptors, the enzymes related to vitamin D metabolism or the transporters of vitamin D, and we discuss the potential correlation of vitamin D status with the vulnerability of neurons to aging and neurodegeneration. Finally, in addition to the current knowledge that defines AD, we suggest that AD could be the result of a long-term hormonal imbalance in which the critical hormone is vitamin D, a secosteroid that has long been misnamed.
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Amyotrophic lateral sclerosis (ALS) is an incurable paralytic disorder primarily typified by the selective and progressive degeneration of motoneurons in the brain and spinal cord. ALS causes muscle wasting and atrophy, resulting eventually in respiratory failure and death within 3-5 years of diagnosis. Vitamin D is a potent secosteroid hormone with diverse biological functions that include protection against neuronal damage. The detrimental consequences of vitamin D dietary deficiency have been documented in other neurodegenerative diseases. However, the protective effect of vitamin D on motoneuron and the influence of its levels on disease course remains elusive. Here we found that the biologically active form of vitamin D significantly potentiated the effect of neurotrophic factors and prevented motoneurons from a Fas-induced death, while electrophysiological properties of motoneurons were not affected. In ALS patients, we report that a severe vitamin D deficiency accelerates by 4 times the rate of decline and were associated with a marked shorter life expectancy. Our findings support a neuroprotective function of vitamin D on motoneurons and propose vitamin D as a reliable prognostic factor of ALS.
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Significance Vitamin D plays an important role in regulating the immune system in health and disease and may be beneficial for patients with multiple sclerosis. It prevents CNS autoimmunity in mice by an incompletely understood mechanism. The present study is a systematic evaluation of the vitamin D effects on T lymphocytes at each step of their journey to the CNS. The data demonstrate that vitamin D does not affect generation of pathogenic cells but prevents their presence in the CNS. Unlike current long-acting drugs that impair immune cell trafficking, the effect of vitamin D is quickly reversed after treatment cessation, which could prove advantageous when immune function needs to be reestablished in the setting of infection.
Article
Objective: Results from studies examining associations between serum 25-hydroxyvitamin D (25(OH)D) concentrations and depressive symptoms are equivocal. We investigated the relationship between serum 25(OH)D concentrations and symptoms of depression, anxiety and stress in a cross-sectional analysis of a population-based sample of young adults participating in the Western Australian Pregnancy Cohort (Raine) Study. Methods: Participants provided a blood sample at the 20-year follow-up (March 2010-April 2012) for the measurement of serum 25(OH)D concentrations. Mental health symptoms were assessed using the 21-item Depression Anxiety Stress Scales (DASS-21). Associations between serum 25(OH)D concentrations and total DASS-21 scores and subscale scores of depression, anxiety and stress were explored in males and females using negative binomial regression, adjusting for age, race, body mass index (BMI) and physical activity (n=735). Models examining subscale scores were also adjusted for the other subscale scores. Results: After adjusting for confounders, an increase in serum 25(OH)D concentrations of 10 nmol/L decreased total DASS-21 scores in males by 9% (rate ratio (RR) 0.91; 95%CI 0.87,0.95; p<0.001) and depression subscale scores in males by 8% (RR 0.92; 95%CI 0.87,0.96; p=0.001). However, in adjusted models there were no significant associations between serum 25(OH)D concentrations and symptoms of anxiety and stress in males. There were no significant associations between serum 25(OH)D concentrations and symptoms of depression, anxiety and stress in females. Conclusions: We found an association between serum 25(OH)D concentrations and symptoms of depression, but not anxiety and stress, in males. Randomised controlled trials are necessary to determine any benefit of vitamin D supplementation in the prevention and treatment of depressive symptoms in young adults.
Article
Ninety percent of the elderly population has a vitamin D hypovitaminosis, and several lines of evidence suggest that there might be a potential causal link between Alzheimer's disease (AD) and a non-sufficient supply with vitamin D. However, the mechanisms linking AD to vitamin D have not been completely understood. The aim of our study is to elucidate the impact of 25(OH) vitamin D3 on amyloid precursor protein processing in mice and N2A cells utilizing very moderate and physiological vitamin D hypovitaminosis in the range of 20-30% compared to wild-type mice. We found that already under such mild conditions, amyloid-β peptide (Aβ) is significantly increased, which is caused by an increased β-secretase activity and BACE1 protein level. Additionally, neprilysin (NEP) expression is downregulated resulting in a decreased NEP activity further enhancing the effect of decreased vitamin D on the Aβ level. In line with the in vivo findings, corresponding effects were found with N2A cells supplemented with 25(OH) vitamin D3. Our results further strengthen the link between AD and vitamin D3 and suggest that supplementation of vitamin D3 might have a beneficial effect in AD prevention. © 2013 S. Karger AG, Basel.
Article
There is growing evidence that vitamin D is a neuroactive steroid capable of regulating multiple pathways important for both brain development and mature brain function. In particular, there is evidence from rodent models that prenatal vitamin D deficiency alters the development of dopaminergic pathways and this disruption is associated with altered behavior and neurochemistry in the adult brain. Although the presence of the vitamin D receptor (VDR) has been noted in the human substantia nigra, there is a lack of direct evidence showing that VDR is present in dopaminergic cells. Here we confirm that the VDR is present in the nucleus of tyrosine hydroxylase (TH)-positive neurons in both the human and rat substantia nigra, and it emerges early in development in the rat, between embryonic day 12 (E12) and E15. Consistent evidence based on immunohistochemistry, real-time PCR and western blot confirmed a pattern of increasing VDR expression in the rat midbrain until weaning. The nuclear expression of VDR in TH-positive neurons during critical periods of brain development suggests that alterations in early life vitamin D status may influence the orderly development of dopaminergic neurons.
Article
The currently available drugs for treatment of Alzheimer's disease are symptomatic and only temporarily slow down the natural history of the disease process. Recently, its has been proposed that the combination of memantine with vitamin D, a neurosteroid hormone, may prevent amyloid-beta and glutamate neurotoxicity. Here, our purpose was to examine the potential protective effects of memantine and vitamin D against amyloid-beta peptide and glutamate toxicity in cortical neuronal cultures. We provide the first evidence that cortical axons degenerate less after exposure to amyloid-beta peptide or glutamate in microfluidic neuronal cultures enriched with memantine plus vitamin D compared to control medium and cultures enriched with only memantine or only vitamin D. The reported synergistic neuroprotective effect of memantine plus vitamin D -the combination originating an effect stronger than the sum- corroborate previous clinical finding that Alzheimer's disease patients using this drug combination have improved cognition. This finding reinforces the pharmacological potential of a new drug combining memantine plus vitamin D for the treatment or the prevention of Alzheimer's disease.
Article
Multiple sclerosis (MS) is an incurable inflammatory demyelinating disease. We investigated one calcitriol dose plus vitamin D3 (calcitriol/+D) as a demyelinating disease treatment in experimental autoimmune encephalomyelitis (EAE). Evidence that calcitriol-vitamin D receptor pathway deficits may promote MS, and data showing calcitriol enhancement of autoimmune T cell apoptosis provided the rationale. Whereas vitamin D3 alone was ineffective, calcitriol/+D transiently increased central nervous system (CNS) Helios(+)FoxP3(+) T cells and sustainably decreased CNS T cells, pathology, and neurological deficits in mice with EAE. Calcitriol/+D, which was more effective than methylprednisolone, has potential for reversing inflammatory demyelinating disease safely and cost-effectively.
Article
In addition to the well-known effects of vitamin D (VitD) in maintaining bone health, there is increasing appreciation that this vitamin may serve important roles in other organs and tissues, including the brain. Given that VitD deficiency is especially widespread among the elderly, it is important to understand how the range of serum VitD levels that mimic those found in humans (from low to high) affects the brain during aging from middle-age to old-age. To address this issue, twenty-seven male F344 rats were split into three groups and fed isocaloric diets containing low (100IU/kg food), control (1000IU/kg food), or high (10000IU/kg food) VitD beginning at middle-age (12 months) and continued for a period of 4-5months. We compared the effects of these dietary VitD manipulations on oxidative and nitrosative stress measures in posterior brain cortices. The low VitD group showed global elevation of 3-nitrotyrosine (3-NT) compared to control and high VitD treated groups. Further investigation showed that this elevation may involve dysregulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and NF-κB mediated transcription of inducible nitric oxide synthase (iNOS) as indicated by translocation of NF-κB to the nucleus and elevation of iNOS levels. Proteomic techniques were used to provide insights into potential mechanisms underlying these effects. Several brain proteins were found at significantly elevated levels in low VitD group compared to the control and high VitD groups. Three of these proteins, 6-phosphofructokinase, triosephosphate isomerase, and pyruvate kinase, are involved directly in glycolysis. Two others, peroxiredoxin-3 and DJ-1/PARK7, have peroxidase activity and are found in mitochondria. Peptidyl-prolyl cis-trans isomerase A (PPIA or cyclophilin A) has been shown to have multiple roles including protein folding, regulation of protein kinases and phosphatases, immunoregulation, cell signaling, and redox status. Together, these results suggest that dietary VitD deficiency contributes to significant nitrosative stress in brain and may promote cognitive decline in middle-aged and elderly adults.
Article
1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits production of IL-12, a cytokine involved in the development of Th1 cells and in the pathogenesis of Th1-mediated autoimmune diseases. Here, we show that 1,25(OH)2D3 and a non-hypercalcemic analogue are selective and potent inhibitors of Th1 development in vitro and in vivo without inducing a deviation to the Th2 phenotype. Administration of 1,25(OH)2D3 or its analogue prevents chronic-relapsing experimental allergic encephalomyelitis (CR-EAE) induced by the myelin oligodendrocyte glycoprotein (MOG) peptide 35 – 55 (MOG35 – 55) in Biozzi AB / H mice. The inhibition of EAE induction is associated with a profound reduction of MOG35 – 55-specific proliferation and Th1 cell development. Importantly, the non-hypercalcemic analogue also provides long-term protection from EAE relapses induced by immunization with spinal cord homogenate when administered for a short time at symptom onset or even after the first peak of disease. Neuropathological analysis shows a reduction of inflammatory infiltrates, demyelinated areas and axonal loss in brains and spinal cords of treated mice. These resuls indicate that inhibition of IL-12-dependent Th1 cell development is associated with effective treatment of CR-EAE and suggest the feasibility of an approach based on low molecular weight inhibitors of IL-12 production in the treatment of multiple sclerosis.
Article
Data are presented to suggest that a geographical predisposing factor (G.P.F.) in multiple sclerosis (M.S.) may reflect regional dietary differences, and, further, that this factor is directly related to milk production or consumption. A number of biochemical hypotheses are proposed which would predict a resultant weakened blood-brain barrier or immunological defence, or the production of defective myelin, which would then increase susceptibility to the ætiological agent, possibly a virus. From the standpoint of brain development, two different ideas emerge—one, that differences in the composition of bovine and human milk, particularly during weaning, lead to the G.P.F.; the other, that drinking of milk beyond the normal nursing period is detrimental. More epidemiological studies are needed, with emphasis on diet, especially during periods of rapid brain development. Cow's milk may be an unfortunate substitute for human milk in infancy or a risky food source thereafter, or both. Epidemiological data raise these questions but do not provide ready answers. The milk correlation could be spurious, but at least ideas based on such a correlation pay attention to the most important epidemiological clue in M.S.—namely, the geographical distribution of the disease.
Article
Background Although the morbidity and mortality of vitamin D deficiency are well known in the elderly and among children, doctors are unlikely to consider it as a diagnosis in young adults, even when it is symptomatic. Numerous additional examinations are thus unnecessarily prescribed, while diagnosis is delayed. After observing several cases of severe vitamin D deficiency among women aged 18 to 49 years who wore concealing clothing, we conducted an investigation of the prevalence of this vitamin deficiency in this community. We asked ourselves 2 questions: What proportion of women in this population has a vitamin D deficiency and how severe is it? Are general practitioners (GPs) aware of this problem? Methods A cross-sectional study was conducted in Lyon, located at a latitude 45N. We included women aged 18 to 49 years, who wore concealing clothes, and consulted their GP from November 2005 through March 2006 and had no disease likely to cause hypovitaminosis D. Physicians completed a questionnaire and collected serum for a vitamin 25 (OH)D assay. We looked for correlations between vitamin D deficiency and several factor: ages, parity, associated diseases, and clinical signs. Results The study included 96 women. Defining hypovitaminosis D at a threshold of 53 nmol/L or 75 nmol/L, we found a prevalence of 99%, and 72.6% of the women had symptoms. Using a stricter threshold of 30 nmol/L, below which secondary hyperparathyroidism can appear and reduce bone mass, we found a prevalence of 82.5%, 71% of whom were symptomatic. The failure to prescribe vitamin D supplementation during the previous 3 months for 99% of these women indicates that GPs are not aware of this issue. Conclusion These results highlight the endemic character of vitamin D deficiency in a population of young women of childbearing age, usually in good health. GPs must be involved in targeted activities to screen for and prevent vitamin D deficiency among this population, because food sources provide minimal quantities of vitamin D.
Article
Background/aims: The beta amyloid aggregations present in Alzheimer's disease affect neurons through various toxic alterations. The aim of this study was to determine the expression of the vitamin D receptor (VDR), 25-hydroxyvitamin D3 24-hydroxylase (an accelerator of vitamin D catabolism), and the L-type voltage-sensitive calcium channel A1C (LVSCC-A1C) in hippocampal neurons in response to beta amyloid and vitamin D treatments to test the protective effects of vitamin D and the probable effects of beta amyloid on vitamin D catabolism. Methods: The expression of the VDR, 24-hydroxylase (24OHase) and LVSCC-A1C mRNAs were studied using quantitative real-time polymerase chain reaction, and the cytotoxicity levels were determined by an ELISA in primary hippocampal neuron cultures prepared from Sprague-Dawley rat embryos. Results: Our results demonstrated that beta amyloid suppressed the expression of VDR mRNA and induced the expression of 24OHase and LVSCC-A1C mRNAs. Conclusion: Beta amyloid may disrupt the vitamin D-VDR pathway and cause defective utilization of vitamin D by suppressing the level of the VDR and elevating the level of 24OHase.
Article
Exposure to stressful life events is associated with the onset of major depression and increases the risk of cardiac morbidity and mortality. While recent evidence has indicated the existence of an interrelationship between local vitamin D (VD) metabolism and many aspects of human physiology including brain and heart function, much is still unknown concerning the biological link between VD signaling and stress-induced depressive behavior and cardiac dysfunction. In the present study, we observed the VD intracrine system in the hippocampus and myocardium of chronic unpredictable mild stress (CUMS) exposed rats. After 4 weeks of CUMS procedure, rats were induced to a depressive-like state and the cytochromes P450 enzymes involved in VD activating and catabolizing (CYP27B1 and CYP24A1 respectively) and VD receptor (VDR) were assessed by real time RT-PCR and western blot in the hippocampus, myocardium and kidney. In the hippocampus of depressed rats, CYP27B1, CYP24A1 and VDR expression were significantly increased and the local status of 1,25-dihydroxyvitamin D (1,25(OH)2D) was higher compared with controls. Furthermore, hippocampal mRNA levels of VD target genes (calbindin-d28k, neurotrophin-3) and RXRα (heterodimeric partner of VDR) were upregulated in response to chronic stress. Similar to the hippocampus, CUMS also induced CYP27B1/CYP24A1/VDR expression in the myocardium. However, renal metabolism of VD and serum1,25(OH)2D status were unchanged. Meanwhile, sertraline treatment could partly normalize the stress-induced alterations of VD metabolism. In conclusion, this study firstly showed a co-elevated expression of CYP27B1/CYP24A1/VDR in both the hippocampus and myocardium of CUMS rats, which suggests VD signaling may be involved in the compensatory mechanism that protect from stress-induced deteriorating effects on the brain and heart.
Article
1α,25-dihydroxyvitamin D3 [1,25D] is recognized as a steroid hormone that rapidly elicits intracellular signals in various tissues. In skeletal myoblasts, we have previously demonstrated that one of the 1,25D -induced non-genomic effects is the upstream stimulation of MAPKs through Src activation. In this work, the data obtained suggest that the classical receptor of vitamin D (VDR) participates in non-transcriptional actions of 1,25D. We significantly reduced VDR expression by infection of C2C12 murine myoblasts with lentiviral particles containing the pLKO.1 plasmid with information to express a shRNA against mouse VDR. In these cells (C2C12-shVDR), Western blot analyses show that 1,25D-induced p38 MAPK activation and Src tyr416 phosphorylation were abolished. In addition, 1,25D-dependent activity of ERK1/2 was diminished in cells lacking VDR but to a lesser extent (∼ - 60%). Phosphorylation of Akt by 1,25D, recently demonstrated in C2C12 cells, in the present work also appeared to be partially dependent on VDR expression (∼ 50% in C2C12-shVDR cells). Our results indicate that VDR is involved in 1,25D-induced rapid events related to survival/proliferation responses in skeletal muscle cells, providing relevant information on the mechanism of initiation of the non-genomic hormone signal. The participation of a VDR-independent non-genomic mechanism of action should also be taken into consideration.
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This study evaluated prevalence and risk factors for vitamin D deficiency among children with epilepsy on long-term antiepileptic drugs treated in South Queensland, Australia. Children with epilepsy seen in a tertiary neurology clinic were contacted requesting bone health blood tests during winter of 2011. Vitamin D deficiency was defined as 25-hydroxy vitamin D levels <20 ng/mL, and insufficiency between 21 and 29 ng/mL. One hundred thirty letters were sent, with 111 (85%) subsequently having blood tests performed. Vitamin D deficiency was identified in 24 (22%) of 111 and an additional 45 (41%) of 111 had vitamin D insufficiency. Multiple logistic regression analysis identified children on >2 antiepileptic drugs or with underlying genetic etiologies were more likely to have vitamin D deficiency. High proportion of children on long-term antiepileptic drugs in Queensland risk vitamin D deficiency and insufficiency despite living in the subtropics. Vitamin D monitoring and supplementation is important in the management of children on long-term antiepileptic drugs requiring tertiary care in Queensland.
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Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental, and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for MS.
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Vitamin D receptor (VDR) and the enzymes involved in bioactivation of vitamin D, shown to be expressed in the central nervous system, particularly in areas affected by neurodegenerative disorders, especially in hippocampus. We showed that amyloid beta (Aβ) pathology includes VDR protein depletion and vitamin D-VDR pathway disruption either induced by Aβ or by VDR siRNA have very similar effects on cortical neurons. The goal of this study is to show the presence of 25 hydroxy vitamin D3-24 hydroxylase (24OHase) which is essential for vitamin D catabolism in hippocampal and cortical neurons. Additional goal is to compare the expression pattern of VDR and 24OHase both in hippocampal and in cortical neurons and to investigate the effects of VDR suppression in hippocampal neurons in order to see whether similar mechanisms work in hippocampus and cerebral cortex. Primary neuronal cultures were prepared from Sprague-dawley rat embryos. qRT-PCR was performed to determine VDR, 24OHase, and LVSCC-A1C mRNA expression levels. Cytotoxicity levels were determined by ELISA. Our findings illustrate that 24OHase mRNA was present both in hippocampal and in cortical neurons. VDR and 24OHase mRNA were higher in hippocampal neurons than the cortical ones. LVSCC-A1C mRNA levels increased in hippocampal neurons when VDR is down-regulated. Our results indicate that hippocampal neurons response to VDR suppression similar as cortical neurons, regarding calcium channel regulation. Higher gene expression of 24OHase and VDR might indicate "higher requirement of vitamin D" in hippocampus and potential consequences of vitamin D deficiency in cognitive decline, neurodegeneration, and Alzheimer's disease.
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Vitamin D deficiency and rickets are major health problems in developing countries. Congenital rickets is a rare form of rickets. Maternal vitamin D deficiency is the most important risk factor for vitamin D deficiency and rickets in newborns and early infancy. In this report, we presented a two-monthold infant with seizures while hospitalized for pulmonary infection. Finally, congenital rickets due to maternal vitamin D deficiency was diagnosed.