cholecalciferol and Demyelinating-Diseases

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.

Topics: Animals; Axons; Axotomy; Cervical Vertebrae; Cholecalciferol; Demyelinating Diseases; Drug Evaluation, Preclinical; Ergocalciferols; Gene Expression Regulation; Humans; Muscle, Skeletal; Nerve Fibers, Myelinated; Nerve Regeneration; Neuroprotective Agents; Peroneal Nerve; Rats; Spinal Cord Injuries; Vitamin D

There is increasing evidence linking vitamin D deficiency to both susceptibility to, and severity of, multiple sclerosis (MS). Patients with the clinically isolated syndrome represent the initial presentation of a demyelinating disorder, and those with asymptomatic lesions on magnetic resonance imaging (MRI) are at risk of progression to clinically definite MS. The aims of this study are to examine the immunologic effects of vitamin D in both healthy individuals and in patients with clinically isolated syndrome, and in the latter group the effects on disease progression assessed by MRI and clinical measures.. This is a single-center double-blind randomized placebo-controlled clinical trial. The primary endpoint is the immunologic effects of two doses of vitamin D compared with placebo over 24 weeks in both healthy control participants and patients presenting with the clinically isolated syndrome. Healthy control participants (n = 39) and patients with clinically isolated syndrome (n = 45) will be randomized to one of three arms, namely 1) vitamin D 5,000 IU daily, 2) vitamin D 10,000 IU daily, or 3) placebo, and followed up for 24 weeks. In both patients and healthy control participants, the primary outcome will be immunologic measures of the frequency of CD4 T-cell subsets and cytokine responses in peripheral blood mononuclear cells, assessed at baseline, and after 16 and 24 weeks of treatment. Secondary endpoints, in the patients with clinically isolated syndrome, will be relapse activity, and the number of new T2 lesions and gadolinium-enhancing lesions assessed by MRI in the two vitamin D-treated groups compared with the placebo-treated group over the 24 weeks of the study.. EU Clinical Trials Register: EudraCT: 2012-000635-68. ClinicalTrials.gov identifier: NCT01728922.

Topics: Biomarkers; Brain; CD4 Lymphocyte Count; Cholecalciferol; Clinical Protocols; Cytokines; Demyelinating Diseases; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Healthy Volunteers; Humans; Ireland; Leukocytes, Mononuclear; Magnetic Resonance Imaging; Multiple Sclerosis; Research Design; Time Factors; Treatment Outcome; Vitamin D

In the central nervous system (CNS) the main proteins of myelin are proteolipid protein (PLP), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and CNPase. Myelin oligodendrocyte glycoprotein is a minor component of the myelin sheath, but is an important autoantigen linked to the pathogenesis of multiple sclerosis (MS). CNPase is expressed exclusively by oligodendrocytes in the CNS, and the appearance of CNPase seems to be one of the earliest events of oligodendrocyte differentiation and myelination. In this study the effects of vitamin D on total protein concentration, CNPase and MOG expression in the cerebral cortex of the murine model of cuprizone-induced demyelination was investigated. The mice were treated by cuprizone for five weeks in order to induce demyelination. The mice were then divided into 3 groups. The first group was injected intraperitoneally (IP) with vitamin D diluted in olive oil in the amount of 5 µg/kg/daily body weight. The second group (SHAM) was injected IP with olive oil and the third group was left without any injection as the control group (n = 11 for each group). After five weeks the mice were killed and the cerebral cortex was collected and the expression of CNPase and MOG was studied by Western blot. Total protein concentration in the vitamin D injected, SHAM and control groups were 0.918 ± 0.003, 0917 ± 0.004 and 0.916 ± 0.004 g/l, respectively (p > 0.05). However, a significant increase in the MOG and CNPase expression was seen in vitamin D injected group as compared to SHAM and control groups. It is concluded that vitamin D plays a role in the process of remyelination by increasing MOG and CNPase expression in the cortex.

Topics: Animals; Cerebral Cortex; Cholecalciferol; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice; Mice, Inbred BALB C; Myelin Basic Protein; Myelin-Oligodendrocyte Glycoprotein; Oligodendroglia

Vitamin D is emerging as a probably important environmental risk factor in multiple sclerosis, affecting both susceptibility and disease progression. It is not known to what extent this effect is due to a modulation of peripheral lymphocyte function, or to intrathecal effects of vitamin D. We investigated the effect of dietary vitamin D3 content on de/remyelination in the cuprizone model, which is a well established toxic model of demyelination, with no associated lymphocyte infiltration. The mice received diets either deficient of (<50 IU/kg), or supplemented with low (500 IU/kg), high (6200 IU/kg) or very high (12500 IU/kg) amounts of vit D3. Cuprizone (0.2%) was added to the diet for six weeks, starting two weeks after onset of the experimental diets. Mouse brain tissue was histopathologically evaluated for myelin and oligodendrocyte loss, microglia/macrophage activation, and lymphocyte infiltration after six weeks of cuprizone exposure, and two weeks after discontinuation of cuprizone exposure. High and very high doses of vitamin D3 significantly reduced the extent of white matter demyelination (p = 0.004) and attenuated microglia activation (p = 0.001). No differences in the density of oligodendrocytes were observed between the diet groups. Two weeks after discontinuation of cuprizone exposure, remyelination was only detectable in the white matter of mice receiving diets deficient of or with low vitamin D3 content. In conclusion, high dietary doses of vitamin D3 reduce the extent of demyelination, and attenuate microglia activation and macrophage infiltration in a toxic model of demyelination, independent of lymphocyte infiltration.

Topics: Animals; Cholecalciferol; Cuprizone; Demyelinating Diseases; Dietary Supplements; Dose-Response Relationship, Drug; Female; Macrophages; Mice; Mice, Inbred C57BL; Microglia; Myelin Sheath; T-Lymphocytes

Cognitive deficits have been observed in patients with multiple sclerosis (MS) due to hippocampal insults. Antioxidant vitamins D and E are suggested for patients suffering from neurodegenerative diseases like MS, while their mechanisms of action are not well understood. Here, we have tried to study the effects of these vitamins on demyelination, cell death, and remyelination of rat hippocampus following local ethidium bromide (EB) injection. Animals received 100 mg/kg vitamin E or 5 microg/kg of vitamin D3 for 2, 7, or 28 days. The extent of demyelination, myelin staining intensity, and expression of myelin basic protein and caspase-3 were investigated using histological and immunoblotting verification. Administration of EB alone caused demyelination, cell death, and afterward an endogenous repair. Vitamins E and D3 reduced the EB-induced damage and increased the endogenous remyelination of hippocampus. Although the anti-apoptotic effect of these vitamins and protection against demyelination were predictable based on their antioxidant effect, our results indicated the positive effect of vitamins E and D3 on process of remyelination by endogenous progenitor cells and supported their possible therapeutic effects in the context of demyelinating diseases like MS.

Topics: Animals; Antioxidants; Apoptosis; Caspase 3; Cholecalciferol; Demyelinating Diseases; Enzyme Inhibitors; Ethidium; Hippocampus; Humans; Male; Myelin Basic Protein; Nerve Regeneration; Rats; Rats, Sprague-Dawley; Vitamin E; Vitamins

Vitamin D is important for bone health and immune regulation, and has been shown to be low in multiple sclerosis (MS). We sought to determine the effect of over the counter low dose cholecalciferol (LDC) and high dose ergocalciferol (HDE) on the vitamin D levels in MS patients.. We retrospectively evaluated serum 25-hydroxy-vitamin D [25(OH)D] levels of 199 patients (CIS, n = 32; RRMS, n = 115; PPMS, n = 10; SPMS, n = 16; Transverse Myelitis (TM), n = 9; other neurological diseases, n = 16) attending our clinic between 2004 and 2008. We examined the change in 25(OH)D levels in 40 MS patients who took either LDC (< or =800 IU/day) or HDE (50,000 IU/day for 7-10 days, followed by 50,000 IU weekly or biweekly).. The average 25(OH)D level was 71 +/- 39 nmol/L (Mean +/- SD), and 167(84%) patients had insufficient levels (< or =100 nmol/L) of 25(OH)D. The patients supplemented with LDC did not have a significant increase in their 25(OH)D levels. However, 25(OH)D levels increased by 42 nmol/L (P = 0.01) in the patients originally taking LDC and then prescribed HDE. Optimal levels (> or =100 nmol/L) were only achieved in less than 40% of patients.. We conclude that large numbers of patients with MS and TM in our cohort are deficient in vitamin D. HDE significantly elevated 25(OH)D levels in MS patients and was more effective at increasing 25(OH)D levels than LDC. Prospective studies are required to determine appropriate dosing regimen to achieve optimal levels in the majority of MS patients and to ascertain the safety, immunological response, and ultimately the clinical efficacy of vitamin D replacement therapy.

Topics: Adult; Cholecalciferol; Demyelinating Diseases; Dose-Response Relationship, Drug; Ergocalciferols; Female; Humans; Longitudinal Studies; Male; Middle Aged; Multiple Sclerosis; Retrospective Studies; Vitamin D Deficiency; Vitamins