Cholecalciferol (Vitamin D3) Reduces Rat Neuropathic Pain by Modulating Opioid Signaling.

The impact of vitamin D on sensory function, including pain processing, has been receiving increasing attention. Indeed, vitamin D deficiency is associated with various chronic pain conditions, and several lines of evidence indicate that vitamin D supplementation may trigger pain relief. However, the underlying mechanisms of action remain poorly understood. We used inflammatory and non-inflammatory rat models of chronic pain to evaluate the benefits of vitamin D3 (cholecalciferol) on pain symptoms. We found that cholecalciferol supplementation improved mechanical nociceptive thresholds in monoarthritic animals and reduced mechanical hyperalgesia and cold allodynia in a model of mononeuropathy. Transcriptomic analysis of cerebrum, dorsal root ganglia, and spinal cord tissues indicate that cholecalciferol supplementation induces a massive gene dysregulation which, in the cerebrum, is associated with opioid signaling (23 genes), nociception (14), and allodynia (8), and, in the dorsal root ganglia, with axonal guidance (37 genes) and nociception (17). Among the identified cerebral dysregulated nociception-, allodynia-, and opioid-associated genes, 21 can be associated with vitamin D metabolism. However, it appears that their expression is modulated by intermediate regulators such as diverse protein kinases and not, as expected, by the vitamin D receptor. Overall, several genes-Oxt, Pdyn, Penk, Pomc, Pth, Tac1, and Tgfb1-encoding for peptides/hormones stand out as top candidates to explain the therapeutic benefit of vitamin D3 supplementation. Further studies are now warranted to detail the precise mechanisms of action but also the most favorable doses and time windows for pain relief.

Vitamin D Improves Neurogenesis and Cognition in a Mouse Model of Alzheimer's Disease.

The impairment of hippocampal neurogenesis at the early stages of Alzheimer's disease (AD) is believed to support early cognitive decline. Converging studies sustain the idea that vitamin D might be linked to the pathophysiology of AD and to hippocampal neurogenesis. Nothing being known about the effects of vitamin D on hippocampal neurogenesis in AD, we assessed them in a mouse model of AD. In a previous study, we observed that dietary vitamin D supplementation in female AD-like mice reduced cognitive decline only when delivered during the symptomatic phase. With these data in hand, we wondered whether the consequences of vitamin D administration on hippocampal neurogenesis are stage-dependent. Male wild-type and transgenic AD-like mice (5XFAD model) were fed with a diet containing either no vitamin D (0VD) or a normal dose of vitamin D (NVD) or a high dose of vitamin D (HVD), from month 1 to month 6 (preventive arm) or from month 4 to month 9 (curative arm). Working memory was assessed using the Y-maze, while amyloid burden, astrocytosis, and neurogenesis were quantified using immunohistochemistry. In parallel, the effects of vitamin D on proliferation and differentiation were assayed on primary cultures of murine neural progenitor cells. Improved working memory and neurogenesis were observed when high vitamin D supplementation was administered during the early phases of the disease, while a normal dose of vitamin D increased neurogenesis during the late phases. Conversely, an early hypovitaminosis D increased the number of amyloid plaques in AD mice while a late hypovitaminosis D impaired neurogenesis in AD and WT mice. The observed in vivo vitamin D-associated increased neurogenesis was partially substantiated by an augmented in vitro proliferation but not an increased differentiation of neural progenitors into neurons. Finally, a sexual dimorphism was observed. Vitamin D supplementation improved the working memory of males and females, when delivered during the pre-symptomatic and symptomatic phases, respectively. Our study establishes that (i) neurogenesis is improved by vitamin D in a male mouse model of AD, in a time-dependent manner, and (ii) cognition is enhanced in a gender-associated way. Additional pre-clinical studies are required to further understand the gender- and time-specific mechanisms of action of vitamin D in AD. This may lead to an adaptation of vitamin D supplementation in relation to patient's gender and age as well as to the stage of the disease.

Vitamin D and cognition in older adults: international consensus guidelines.

Hypovitaminosis D, a common condition in older adults, is associated with brain changes and dementia. Given the fast growing contribution of literature in this research field, clear guidance is needed for clinicians and researchers. International experts met at the invitational summit on "Vitamin D and cognition in older adults" in Boston, MA, July 2013. Based upon literature and expert opinion, the task force focused on key questions on the role of vitamin D in Alzheimer disease and related disorders. Each question was discussed and voted using a Delphi-like approach. Experts reached agreement that hypovitaminosis D increases the risk of cognitive decline and dementia in older adults, may alter the clinical presentation as a consequence of related comorbidities, but should not be used thus far as a diagnostic or prognostic biomarker of Alzheimer disease due to lack of specificity and insufficient evidence. Hypovitaminosis D should be screened in this population because of its high prevalence and supplemented, if necessary, but this advice was not specific to cognition. The task force agreed on 5 overarching principles related to vitamin D and cognition in older adults.

Vitamin D, Cognition and Alzheimer's Disease: The Therapeutic Benefit is in the D-Tails.

Since its discovery during the epidemic of rickets in the early 1920s, the physiological effects of vitamin D on calcium/phosphorus homeostasis have been thoroughly studied. Along with the understanding of its actions on skeletal diseases and advances in cellular and molecular biology, this misnamed vitamin has gained attention as a potential player in a growing number of physiological processes and a variety of diseases. During the last 25 years, vitamin D has emerged as a serious candidate in nervous system development and function and a therapeutic tool in a number of neurological pathologies. More recently, experimental and pre-clinical data suggest a link between vitamin D status and cognitive function. Human studies strongly support a correlation between low levels of circulating 25-hydroxyvitamin D (25(OH)D) and cognitive impairment or dementia in aging populations. In parallel, animal studies show that supplementation with vitamin D is protective against biological processes associated with Alzheimer's disease (AD) and enhances learning and memory performance in various animal models of aging and AD. These experimental observations support multiple mechanisms by which vitamin D can act against neurodegenerative processes. However, clinical interventional studies are disappointing and fail to associate increased 25(OH)D levels with improved cognitive outcomes. This review collects the current available data from both animal and human studies and discusses the considerations that future studies examining the effects of vitamin D status on neurocognitive function might consider.

Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer's disease.

BACKGROUND: Increasing evidence suggests a potential therapeutic benefit of vitamin D supplementation against Alzheimer's disease (AD). Although studies have shown improvements in cognitive performance and decreases in markers of the pathology after chronic treatment, the mechanisms by which vitamin D acts on brain cells are multiple and remain to be thoroughly studied. We analyzed the molecular changes observed after 5 months of vitamin D3 supplementation in the brains of transgenic 5xFAD (Tg) mice, a recognized mouse model of AD, and their wild type (Wt) littermates. We first performed a kinematic behavioural examination at 4, 6 and 8 months of age (M4, M6 and M8) followed by a histologic assessment of AD markers. We then performed a comparative transcriptomic analysis of mRNA regulation in the neocortex and hippocampus of 9 months old (M9) female mice. RESULTS: Transcriptomic analysis of the hippocampus and neocortex of both Wt and Tg mice at M9, following 5 months of vitamin D3 treatment, reveals a large panel of dysregulated pathways related to i) immune and inflammatory response, ii) neurotransmitter activity, iii) endothelial and vascular processes and iv) hormonal alterations. The differentially expressed genes are not all direct targets of the vitamin D-VDR pathway and it appears that vitamin D action engages in the crosstalk with estrogen and insulin signaling. The misexpression of the large number of genes observed in this study translates into improved learning and memory performance and a decrease in amyloid plaques and astrogliosis in Tg animals. CONCLUSIONS: This study underlies the multiplicity of action of this potent neurosteroid in an aging and AD-like brain. The classical and non-classical actions of vitamin D3 can act in an additive and possibly synergistic manner to induce neuroprotective activities in a context-specific way.

Mood disorders are associated with a more severe hypovitaminosis D than schizophrenia.

Patients with psychiatric disorders display high levels of hypovitaminosis D (<50nmol/L). It remains unclear whether it is associated with specific diagnoses. To further explore vitamin D status in psychiatric inpatients, 82 individuals with mood disorders or schizophrenia/schizoaffective disorders were included. Hypovitaminosis D was significantly lower in patients with mood disorders than patients with schizophrenia (standardized ß coefficient=0.385, p=0.007). Further studies are warranted to determine specific causes of hypovitaminosis D and the interest of supplementation.

Vitamin D-related changes in intracranial volume in older adults: a quantitative neuroimaging study.

OBJECTIVES: Vitamin D is involved in skeletal and brain health. Recently, serum 25-hydroxyvitamin D (25OHD) concentration was found to be inversely correlated with intracranial volume in younger adults. Since hypovitaminosis D is most common in older adults, our objective was to determine whether this inverse correlation between 25OHD concentration and intracranial volume also occurred in older adults. STUDY DESIGN: Cross-sectional study. MAIN OUTCOME MEASURES: One hundred and ten Caucasian older community-dwellers (mean, 71.7±5.7 years; 45.5% female) received a blood test and an MRI of the brain at the same period. The intracranial volume and the subvolumes of cerebrospinal fluid, total brain, infratentorial brain, supratentorial brain, total white matter, total gray matter, cortical gray matter and subcortical gray matter were measured using FreeSurfer volumetry on T1-weighted images. Vitamin D insufficiency was defined as serum 25OHD<50nmol/L. Age, gender, body mass index, education level, use of vitamin D supplements, season of evaluation, serum concentrations of calcium and thyroid stimulating hormone were used as covariables in the analysis. RESULTS: We found that participants with vitamin D insufficiency (n=41) had greater intracranial volume than those without (1555.0±1379.2cm(3) versus 1488.0±167.4cm(3), P=0.033). Serum 25OHD concentration was cross-sectionally associated with decreased intracranial volume in mm(3) (unadjusted ß=-1194.4, P=0.028), even after adjustment for covariables (adjusted ß=-994.3, P=0.048). We found an inverse correlation of serum 25OHD with intracranial volume (r=-0.21, P=0.028) and the volume of white matter (r=-0.20, P=0.033). The other subvolumes did not correlate with serum 25OHD concentration. CONCLUSIONS: Serum 25OHD concentration was independently and inversely associated with intracranial volume in older adults.

Vitamin D3 potentiates myelination and recovery after facial nerve injury.

Roles of vitamin D on the immune and nervous systems are increasingly recognized. Two previous studies demonstrated that ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) induced functional recovery and increased myelination in a rat model of peroneal nerve transection. The current report assessed whether cholecalciferol was efficient in repairing transected rabbit facial nerves. Animals were randomized into two groups of rabbits with an unilateral facial nerve surgery: the vitamin D group included animals receiving a weekly oral bolus of vitamin D3 (200 IU/kg/day), from day 1 post-surgery; the control group included animals receiving a weekly oral bolus of vehicle (triglycerides). Contralateral unsectioned facial nerves from all experimental animals were used as controls for the histological study. The facial functional index was measured every week while the inner diameter of myelin sheath and the G ratio were quantified at the end of the 3 month experiment. The current report indicates that cholecalciferol significantly increases functional recovery and myelination, after 12 weeks of treatment. To the best of our knowledge, this is the first study investigating the therapeutic benefit of vitamin D supplementation in an animal model of facial paralysis. It paves further the way for clinical trials based on the administration of this steroid in individuals with injured facial nerves.

Auditory velocity discrimination in the horizontal plane at very high velocities.

We determined velocity discrimination thresholds and Weber fractions for sounds revolving around the listener at very high velocities. Sounds used were a broadband white noise and two harmonic sounds with fundamental frequencies of 330 Hz and 1760 Hz. Experiment 1 used velocities ranging between 288°/s and 720°/s in an acoustically treated room and Experiment 2 used velocities between 288°/s and 576°/s in a highly reverberant hall. A third experiment addressed potential confounds in the first two experiments. The results show that people can reliably discriminate velocity at very high velocities and that both thresholds and Weber fractions decrease as velocity increases. These results violate Weber's law but are consistent with the empirical trend observed in the literature. While thresholds for the noise and 330 Hz harmonic stimulus were similar, those for the 1760 Hz harmonic stimulus were substantially higher. There were no reliable differences in velocity discrimination between the two acoustical environments, suggesting that auditory motion perception at high velocities is robust against the effects of reverberation.

[Role of vitamin D in the physiopathology of neurodegenerative diseases]. / Rôle de la vitamine D dans la physiopathologie des maladies neurodégénératives.

The involvement of vitamin D in brain function has been discovered in the past 25 years by epidemiological and fundamental studies. Research on neurodegenerative diseases and their animal or cellular models unveiled converging lines of evidence indicating that hypovitaminosis D is not just an effect of the progression of neurodegenerative diseases, but truly an aggravating co-factor, sometimes very closely related to their physiopathology. Vitamin D is a steroid hormone capable of regulating the expression of hundreds of genes through both genetic and epigenetic mechanisms. This reflects the highly pleiotropic nature of its action in its conventional bone and phosphocalcic metabolism targets. Its role in the central nervous system and neurodegenerative diseases makes no exception to this rule. Here we focus on the identified role and mechanisms of vitamin D in multiple sclerosis, Alzheimer's disease and Parkinson's disease. The important prevalence of hypovitaminosis D under our latitudes in general and in at-risk groups in particular, its easy evaluation and correction, and the results of early clinical studies, suggest that vitamin D supplementation could usefully complement our therapeutic armory to fight these diseases.

[Repairing the spinal cord with vitamin D: a promising strategy]. / La vitamine D au secours du traumatisme médullaire : un espoir à confirmer.

In 2014, a phase II randomised, double blind clinical trial assessing the efficacy of cholecalciferol (vitamin D3) in patients with a cervical trauma will be set up. This trial stems from previous studies showing that vitamin D supplementation improves functional recovery in rat models of peripheral or central nerve injury. In a first series of experiments, we used a rat model of peripheral nerve trauma to demonstrate the therapeutic efficiency of vitamin D. We first demonstrated that ergocalciferol (vitamin D2) increases the number and the diameter of newly formed axons and improves the response of metabosensitive fibers from tibialis muscle, in a model of transected peroneal nerve. Then, we compared vitamin D2 and vitamin D3 and observed that the latter is more efficient. At the dose of 500 IU/kg/day, vitamin D3 induces a dramatic functional recovery. We also demonstrated that vitamin D3 increases the number of preserved or newly formed axons in the proximal end, the mean axon diameter in the distal end, neurite myelination in both the distal and proximal ends as well as the expression of genes involved in axogenesis and myelination. In parallel, we assessed the therapeutic role of vitamin D on the central nervous system. In a first study, using a rat model of spinal cord compression at the T10 thoracic level, we delivered vitamin D3 (cholecalciferol) orally at the dose of 50 IU/kg/day or 200 IU/kg/day. When compared to control animals, vitamin D-treated rats displayed, three months after injury, a significant improvement of ventilatory frequency and a reduction of H reflex indicating functional improvements at three months post-injury. In a second study, we used a rat model of cervical hemisection (C2) with a higher dose of oral vitamin D3 (500 IU/kg/day) delivered weekly, during 12 weeks. We observed an improved locomotor recovery, a reduced spasticity and a significantly higher rate of axons crossing the lesion site in treated animals. However, it must be pointed out that the functional improvement is reduced when vitamin D is provided one week after the trauma.

Cholecalciferol (vitamin D3) improves myelination and recovery after nerve injury.

Previously, we demonstrated i) that ergocalciferol (vitamin D2) increases axon diameter and potentiates nerve regeneration in a rat model of transected peripheral nerve and ii) that cholecalciferol (vitamin D3) improves breathing and hyper-reflexia in a rat model of paraplegia. However, before bringing this molecule to the clinic, it was of prime importance i) to assess which form - ergocalciferol versus cholecalciferol - and which dose were the most efficient and ii) to identify the molecular pathways activated by this pleiotropic molecule. The rat left peroneal nerve was cut out on a length of 10 mm and autografted in an inverted position. Animals were treated with either cholecalciferol or ergocalciferol, at the dose of 100 or 500 IU/kg/day, or excipient (Vehicle), and compared to unlesioned rats (Control). Functional recovery of hindlimb was measured weekly, during 12 weeks, using the peroneal functional index. Ventilatory, motor and sensitive responses of the regenerated axons were recorded and histological analysis was performed. In parallel, to identify the genes regulated by vitamin D in dorsal root ganglia and/or Schwann cells, we performed an in vitro transcriptome study. We observed that cholecalciferol is more efficient than ergocalciferol and, when delivered at a high dose (500 IU/kg/day), cholecalciferol induces a significant locomotor and electrophysiological recovery. We also demonstrated that cholecalciferol increases i) the number of preserved or newly formed axons in the proximal end, ii) the mean axon diameter in the distal end, and iii) neurite myelination in both distal and proximal ends. Finally, we found a modified expression of several genes involved in axogenesis and myelination, after 24 hours of vitamin supplementation. Our study is the first to demonstrate that vitamin D acts on myelination via the activation of several myelin-associated genes. It paves the way for future randomised controlled clinical trials for peripheral nerve or spinal cord repair.

Effect of high-dose vitamin D3 intake on ambulation, muscular pain and bone mineral density in a woman with multiple sclerosis: a 10-year longitudinal case report.

Mounting evidence correlate vitamin D3 (cholecalciferol) supplementation or higher serum levels of vitamin D (25(OH)D) with a lower risk of developing multiple sclerosis (MS), reduced relapse rate, slower progression or fewer new brain lesions. We present here the case of a woman who was diagnosed with MS in 1990. From 1980 to 2000, her ability to walk decreased from ~20 to 1 km per day. Since January 2001, a vitamin D3 supplement was ingested daily. The starting dose was 20 mcg (800 IU)/day and escalated to 100 mcg (4000 IU)/day in September 2004 and then to 150 mcg (6000 IU)/day in December 2005. Vitamin D3 intake reduced muscular pain and improved ambulation from 1 (February 2000) to 14 km/day (February 2008). Vitamin D intake over 10 years caused no adverse effects: no hypercalcaemia, nephrolithiasis or hypercalciuria were observed. Bowel problems in MS may need to be addressed as they can cause malabsorption including calcium, which may increase serum PTH and 1,25(OH)2D levels, as well as bone loss. We suggest that periodic assessment of vitamin D3, calcium and magnesium intake, bowel problems and the measurement of serum 25(OH)D, PTH, Ca levels, UCa/Cr and bone health become part of the integral management of persons with MS.

Seasonal, gestational and postnatal influences on multiple sclerosis: the beneficial role of a vitamin D supplementation during early life.

There is now strong evidence linking vitamin D, the steroid hormone of sunlight, and Multiple Sclerosis (MS). Two of the most intriguing findings are the season of birth and childhood sun exposure effects. They both suggest that a vitamin D deficiency during these critical imprinting periods is a risk factor for MS. After having confirmed that people born in November are at lower risk of developing MS, we devised a mouse model of prenatal vitamin D deficiency. We observed that adult offspring born to vitamin D deficient mothers, when compared to control offspring, developed a striking milder and delayed experimental autoimmune encephalomyelitis (EAE) and permanently overexpressed the vitamin D receptor. This unexpected finding led us to conjecture that the newborns, after having known an in utero vitamin D-deficient environment, were highly sensitive ex utero to cholecalciferol-containing diet and interpreted the postnatal food as a vitamin D enriched environment. To validate this hypothesis, we devised a mouse model of postnatal vitamin D supplementation. Interestingly, using the same EAE model, we demonstrated that a delayed onset and less severe symptoms were displayed by postnatally vitamin D-supplemented mice. The latter finding is in accordance with previous animal studies demonstrating that a postnatal vitamin D deficiency induced an earlier onset and an increased symptom severity of EAE and epidemiological reports describing the importance of an adequate supply of vitamin D during early life.

Upper limits of auditory rotational motion perception.

Three experiments are reported, which investigated the auditory velocity thresholds beyond which listeners are no longer able to perceptually resolve a smooth circular trajectory. These thresholds were measured for band-limited noises, white noise, and harmonic sounds (HS), and in different acoustical environments. Experiments 1 and 2 were conducted in an acoustically dry laboratory. Observed thresholds varied as a function of stimulus type and spectral content. Thresholds for band-limited noises were unaffected by center frequency and equal to that of white noise. For HS, however, thresholds decreased as the fundamental frequency of the stimulus increased. The third experiment was a replication of the second in a reverberant concert hall, which produced qualitatively similar results except that thresholds were significantly higher than in the acoustically dry laboratory.

Vitamin D2 potentiates axon regeneration.

To date, the use of autograft tissue remains the "gold standard" technique for repairing transected peripheral nerves. However, the recovery is suboptimal, and neuroactive molecules are required. In the current study, we focused our attention on vitamin D, an FDA-approved molecule whose neuroprotective and neurotrophic actions are increasingly recognized. We assessed the therapeutic potential of ergocalciferol--the plant-derived form of vitamin D, named vitamin D2--in a rat model of peripheral nerve injury and repair. The left peroneal nerve was cut out on a length of 10 mm and immediately autografted in an inverted position. After surgery, animals were treated with ergocalciferol (100 IU/kg/day) and compared to untreated animals. Functional recovery of hindlimb was measured weekly, during 10 weeks post-surgery, using a walking track apparatus and a numerical camcorder. At the end of this period, motor and sensitive responses of the regenerated axons were calculated and histological analysis was performed. We observed that vitamin D2 significantly (i) increased axogenesis and axon diameter; (ii) improved the responses of sensory neurons to metabolites such as KCl and lactic acid; and (iii) induced a fast-to-slow fiber type transition of the Tibialis anterior muscle. In addition, functional recovery was not impaired by vitamin D supplementation. Altogether, these data indicate that vitamin D potentiates axon regeneration. Pharmacological studies with various concentrations of the two forms of vitamin D (ergocalciferol vs. cholecalciferol) are now required before recommending this molecule as a potential supplemental therapeutic approach following nerve injury.

Combined prenatal and chronic postnatal vitamin D deficiency in rats impairs prepulse inhibition of acoustic startle.

There is growing evidence that 1,25-dihydroxyvitamin D3 is involved in normal brain development. The aim of this study was to examine the impact of prenatal and postnatal hypovitaminosis D on prepulse inhibition (PPI) of acoustic startle in adult rats. We compared six groups of rats: control rats with normal vitamin D throughout life and normal litter size (Litter); control rats with normal vitamin D but with a reduced litter size of two (Control); offspring from reduced litters of vitamin D deplete mothers who were repleted at birth (Birth), repleted at weaning (Weaning) or remained on a deplete diet until 10 weeks of age (Life); or control rats that were placed on a vitamin D-deficient diet from 5 to 10 weeks of age (Adult). All rats were tested in acoustic startle chambers at 5 and 10 weeks of age for acoustic startle responses and for PPI. There were no significant group differences at 5 weeks of age on the acoustic startle response or on PPI. At 10 weeks of age, rats in the Life group only had impaired PPI despite having normal acoustic startle responses. We conclude that combined prenatal and chronic postnatal hypovitaminosis D, but not early life hypovitaminosis D, alters PPI.