vitamin-k-semiquinone-radical and Multiple-Sclerosis

Neurodegenerative disease refers to a group of disorders that predominantly damage the neurons in the brain. Despite significant progress in the knowledge of neurodegenerative diseases, there is currently no disease-modifying drug available. Vitamin K was first established for its involvement in blood clotting, but there is now compelling evidence indicating its role in the neurological system. In particular, the results of recent studies on the effects of vitamin K2 on preventing apoptosis, oxidative stress, and microglial activation in neuron cells through its role in electron transport are very promising against Alzheimer's disease. In addition to its protective effect on cognitive functions, its inhibitory effects on inflammation and α-synuclein fibrillization in Parkinson's disease, which has been revealed in recent years, are remarkable. Although there are many studies on the mechanism and possible treatment methods of neurodegenerative diseases, especially Parkinson's and Alzheimer's disease, studies on the relationship between vitamin K and neurodegenerative diseases are very limited, yet have promising findings. Vitamin K has also been proposed for therapeutic use in multiple sclerosis patients to lower the intensity or to slow down the progression of the disease. Accordingly, the aim of this study is to review the current evidence for the use of vitamin K supplementation in neurodegenerative diseases, in particular Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

Topics: Alzheimer Disease; Humans; Multiple Sclerosis; Neurodegenerative Diseases; Parkinson Disease; Vitamin K

Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K-dependent growth arrest-specific protein 6 (Gas6). Gas6 and the TAMs are abundantly expressed in the nervous system. Gas6, secreted by neurons and endothelial cells, is the sole ligand for Axl. ProteinS1 (ProS1), another vitamin K-dependent protein functions mainly as an anti-coagulant, and independent of this function can activate Tyro3 and Mertk, but not Axl. This review will focus on the role of the TAM receptors and their ligands in the nervous system. We highlight studies that explore the function of TAM signaling in myelination, the visual cortex, neural cancers, and multiple sclerosis (MS) using Gas6

Topics: Animals; Axl Receptor Tyrosine Kinase; Blood Proteins; c-Mer Tyrosine Kinase; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Mice; Multiple Sclerosis; Nervous System; Protein S; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Signal Transduction; Vitamin K

Autoreactive T cells, particularly those characterized by a Th17 phenotype, exert significant influence on the pathogenesis of multiple sclerosis (MS). The present study aimed to elucidate the impact of individual and combined administration of vitamin A and D on neuroinflammation, and microRNAs (miRNAs) involved in T helper (Th)17 development, utilizing a murine model of experimental autoimmune encephalomyelitis (EAE). EAE was induced in C57BL/6 mice, and 3 days prior to immunization, intraperitoneal injections of vitamins A and D or their combination were administered. Th17 cell percentages were determined in splenocytes utilizing intracellular staining and flow cytometry. Furthermore, the expression of Ror γ-t, miR-98-5p and Let-7a-5p, was measured in both splenocytes and spinal cord tissues using RT-PCR. Treatment with vitamin A and D resulted in a reduction in both disease severity in EAE mice. Treated mice showed a decreased frequency of Th17 cells and lower expression levels of IL17 and Ror γ-t in splenocytes and spinal cord. The spinal cord tissues and splenocytes of mice treated with vitamins A, D, and combined A+D showed a significant upregulation of miR-98-5p and Let-7a-5p compared to the EAE group. Statistical analysis indicated a strong negative correlation between miR-98-5p and Let-7a-5p levels in splenocytes and Ror-t expression. Our findings indicate that the administration of vitamins A and D exerts a suppressive effect on neuroinflammation in EAE that is associated with a reduction in the differentiation of T cells into the Th17 phenotype and is mediated by the upregulation of miR-98-5p and Let-7a-5p, which target the Ror γ-t.

Topics: Animals; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Mice; Mice, Inbred C57BL; MicroRNAs; Multiple Sclerosis; Neuroinflammatory Diseases; Nuclear Receptor Subfamily 1, Group F, Member 3; Th17 Cells; Vitamin A; Vitamin K; Vitamins

Vitamin K2 (VK2) belongs to the vitamin K family and comprises a number of subtypes differing in length of side chains consisting of isoprenoid groups (menaquinone-n, MK-n). It is essential for a number of physiological functions although the full spectrum of activity has not yet been elucidated. Due to its role in protection of mitochondrial damage, VK2 could be relevant in preventing disease progress in multiple sclerosis (MS).. We measured VK2 serum levels by the double antibody sandwich Enzyme-linked Immunosorbent Assay (ELISA) technique in MS patients and age and sex matched controls, both under vitamin D supplementation, and related it to disease characteristics and treatment.. Overall, 45 MS patients (31 females and 39 of the relapsing-remitting type) and 29 healthy controls (19 females) were included in the analysis. The MS patients had vastly lower VK2 blood levels than controls (235 ± 100 ng/ml vs. 812 ± 154 ng/ml, respectively). Female patients had significantly lower VK2 levels than males and a decrease with age by approximately 10% per decade was found. The VK2 levels were lower with increasing numbers of attacks per year and were higher in patients with optic nerve lesions. No consistent relationship with medications was detected.. The substantially lower levels of VK2 in MS patients could be due to depletion, lower production in the gut, diminished absorption or, less likely, reduced intake of precursor vitamin K1. The role of VK2 in MS development and progress deserves further study.

Topics: Case-Control Studies; Cross-Sectional Studies; Female; Humans; Male; Multiple Sclerosis; Vitamin K; Vitamin K 2

Multiple sclerosis (MS) is a devastating neurological disease, which is characterized by multifocal demyelinating lesions in the central nervous system. The most abundant myelin lipids are galactosylceramides and their sulfated form, sulfatides, which together account for about 27% of the total dry weight of myelin. In this study we investigated the role of vitamin K in remyelination, by using an animal model for MS, the cuprizone model. Demyelination was induced in C57Bl6/J mice, by feeding them a special diet containing 0.3% cuprizone (w/w) for 6 weeks. After 6 weeks, cuprizone was removed from the diet and mice were allowed to remyelinate for either 1 or 3 weeks, in the absence or presence of vitamin K (i.p. phylloquinone, 2mg, three times per week). Vitamin K enhanced the production of total brain sulfatides, after both 1 week and 3 weeks of remyelination (n = 5, P-values were <0.0001), when compared with the control group. To determine whether or not there is a synergistic effect between vitamins K and D for the production of brain sulfatides, we employed a similar experiment as above. Vitamin K also increased the production of individual brain sulfatides, including d18:1/18:0, d18:1/20:0, d18:1/24:0, and d18:1/24:1 after 3 weeks of remyelination, when compared to the control group. In addition, vitamin D enhanced the production of total brain sulfatides, as well as d18:1/18:0, d18:1/24:0, and d18:1/24:1 sulfatides after 3 weeks of remyelination, but no synergistic effect between vitamins K and D for the production of total brain sulfatides was observed.

Topics: Animals; Brain; Cuprizone; Encephalomyelitis, Autoimmune, Experimental; Galactosylceramides; Male; Mice, Inbred C57BL; Multiple Sclerosis; Neuroprotective Agents; Remyelination; Sulfoglycosphingolipids; Swine; Vitamin D; Vitamin K

Fat-soluble vitamins (A, D, E and K) have properties that could be relevant as modulators of disease activity in multiple sclerosis (MS).. We performed a systematic search on PubMed and Medline up to May 2012, using the search strings 'vitamin A', 'retinol', 'retinal', 'carotenoids', 'vitamin D', 'vitamin E', 'alpha-tocopherol', 'vitamin K' in conjunction with 'multiple sclerosis', 'animal model' and 'experimental autoimmune encephalitis (EAE)'. In addition, the reference lists of the publications identified were examined for further citations of relevance.. There is comprehensive evidence from epidemiological, observational, and experimental studies that vitamin D may be beneficial in MS. Results from small-scale clinical studies are inconclusive, and large-scale, adequately powered, randomized, controlled trials are still lacking. For vitamin D, Oxford Centre for Evidence-Based Medicine level 2c evidence exists for a positive therapeutic effect. Evidence from animal models indicates that all the examined fat-soluble vitamins could have potential as modulators of disease activity in MS. For vitamin A and E, level 4 and 5 evidence exists for a modulatory effect in MS; for vitamin K, too few studies have been conducted to indicate an effect in humans.. Vitamin D is a promising candidate as modulator of disease activity in MS, and controlled studies are currently being conducted. All the fat-soluble vitamins have, however, been demonstrated to be effective in different animal models for the disease, and vitamin A and E have biological properties that could be relevant for MS pathogenesis. Thus, vitamin A and E seem to be promising candidates for future case-control and cohort studies.

Topics: Animals; Clinical Trials as Topic; Disease Models, Animal; Fats; Humans; MEDLINE; Multiple Sclerosis; Observation; PubMed; Vitamin A; Vitamin D; Vitamin E; Vitamin K; Vitamins

There are still questions regarding whether macrophages found in MS lesions are agents of recovery or of destruction. To address this, we examined in aggregate cultures prepared from dissociated embryonic spinal cord tissue, with or without addition of exogenous macrophages, the effect of menadione-induced oxidative stress. Similar to findings of other laboratories, we observed that in the absence of oxidative stress macrophage enrichment promoted myelinogenesis. In macrophage-poor cultures, menadione at 5 microM had very little effect upon the status of the aggregate cultures; however, increasing this to 10 and 20 microM did result in some damage to axons and myelin. By contrast, in macrophage enriched cultures, menadione at a concentration as little as 5 microM caused the complete destruction of the aggregates. We suggest that in neural tissues that have sufficiently high macrophage numbers, oxidative stress results in a positive inflammatory feedback loop that results in massive tissue destruction. We further suggest that what we see in macrophage-enriched aggregates subjected to oxidative stress may represent what happens in the Marburg-type of MS lesion.

Topics: Animals; Cell Death; Cells, Cultured; Fetus; Macrophages; Microscopy, Electron; Multiple Sclerosis; Myelin Sheath; Myelitis; NADPH-Ferrihemoprotein Reductase; Nerve Fibers, Myelinated; Neurons; Neurotoxins; Oligodendroglia; Oxidative Stress; Rats; Rats, Wistar; Spinal Cord; Superoxides; Vitamin K

Topics: Adult; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Neurologic Examination; Neurologic Manifestations; Vitamin K

Topics: Blood Transfusion; Female; Humans; Liver Extracts; Multiple Sclerosis; Pathology; Pregnancy; Pregnancy Complications; Vitamin A; Vitamin K; Vitamins

Topics: Humans; Multiple Sclerosis; Vitamin A; Vitamin K; Vitamins

Topics: Bone Diseases; Disease; Multiple Sclerosis; Osteitis Deformans; Skull; Thiamine Pyrophosphate; Vitamin A; Vitamin K; Vitamins

Topics: Chronic Disease; Humans; Multiple Sclerosis; Psychotherapy, Multiple; Vitamin A; Vitamin K; Vitamins

Topics: Humans; Multiple Sclerosis; Nutrition Therapy; Vitamin A; Vitamin K; Vitamins

Topics: Ammonia; Ammonium Chloride; Ammonium Compounds; Animals; Fats; Humans; Multiple Sclerosis; Quaternary Ammonium Compounds; Sclerosis; Vitamin A; Vitamin K; Vitamins