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DOI: 10.1055/s-0033-1357481
Vitamin K and Brain Function
Publication History
Publication Date:
09 October 2013 (online)
Abstract
One of the fat-soluble vitamins, vitamin K was initially discovered for its role in blood coagulation. Although several vitamin K–dependent hemostatic proteins are particularly important for the brain, other vitamin K–dependent proteins (VKDPs), not associated with blood coagulation, also contribute to the brain function. In addition to the VKDPs, vitamin K participates in the nervous system through its involvement in sphingolipid metabolism, a class of lipids widely present in brain cell membranes. Classically known for their structural role, sphingolipids are biologically potent molecules involved in a wide range of cellular actions. Also, there is growing evidence that the K vitamer, menaquinone-4, has anti-inflammatory activity and offers protection against oxidative stress. Finally, although limited in numbers, reports point to a modulatory role of vitamin K in cognition. This short review presents an overview of the known role of vitamin K in brain function to date.
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References
- 1 Ferland G, Vitamin K. In: Erdman J, Macdonald I, Zeisel S, eds. Present Knowledge in Nutrition. 10th ed. Washington, DC: ILSI Press; 2012: 384-412
- 2 Suttie JW. Vitamin K in Health and Disease. Boca Raton, FL: CRC Press; 2009
- 3 Thijssen HH, Vervoort LM, Schurgers LJ, Shearer MJ. Menadione is a metabolite of oral vitamin K. Br J Nutr 2006; 95 (2) 260-266
- 4 Okano T, Shimomura Y, Yamane M , et al. Conversion of phylloquinone (Vitamin K1) into menaquinone-4 (Vitamin K2) in mice: two possible routes for menaquinone-4 accumulation in cerebra of mice. J Biol Chem 2008; 283 (17) 11270-11279
- 5 Nakagawa K, Hirota Y, Sawada N , et al. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature 2010; 468 (7320) 117-121
- 6 Thijssen HH, Drittij-Reijnders MJ. Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4. Br J Nutr 1994; 72 (3) 415-425
- 7 Carrié I, Portoukalian J, Vicaretti R, Rochford J, Potvin S, Ferland G. Menaquinone-4 concentration is correlated with sphingolipid concentrations in rat brain. J Nutr 2004; 134 (1) 167-172
- 8 Carrié I, Bélanger E, Portoukalian J, Rochford J, Ferland G. Lifelong low-phylloquinone intake is associated with cognitive impairments in old rats. J Nutr 2011; 141 (8) 1495-1501
- 9 Huber AM, Davidson KW, O'Brien-Morse ME, Sadowski JA. Tissue phylloquinone and menaquinones in rats are affected by age and gender. J Nutr 1999; 129 (5) 1039-1044
- 10 Ronden JE, Thijssen HH, Vermeer C. Tissue distribution of K-vitamers under different nutritional regimens in the rat. Biochim Biophys Acta 1998; 1379 (1) 16-22
- 11 Cheng T, Liu D, Griffin JH , et al. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 2003; 9 (3) 338-342
- 12 Liu D, Cheng T, Guo H , et al. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat Med 2004; 10 (12) 1379-1383
- 13 Thiyagarajan M, Fernández JA, Lane SM, Griffin JH, Zlokovic BV. Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J Neurosci 2008; 28 (48) 12788-12797
- 14 Yesilirmak DC, Kumral A, Tugyan K , et al. Effects of activated protein C on neonatal hypoxic ischemic brain injury. Brain Res 2008; 1210: 56-62
- 15 Hirose K, Okajima K, Taoka Y , et al. Activated protein C reduces the ischemia/reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation. Ann Surg 2000; 232 (2) 272-280
- 16 Yamauchi T, Sakurai M, Abe K, Takano H, Sawa Y. Neuroprotective effects of activated protein C through induction of insulin-like growth factor-1 (IGF-1), IGF-1 receptor, and its downstream signal phosphorylated serine-threonine kinase after spinal cord ischemia in rabbits. Stroke 2006; 37 (4) 1081-1086
- 17 Zlokovic BV, Zhang C, Liu D, Fernandez J, Griffin JH, Chopp M. Functional recovery after embolic stroke in rodents by activated protein C. Ann Neurol 2005; 58 (3) 474-477
- 18 Zhong Z, Ilieva H, Hallagan L , et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J Clin Invest 2009; 119 (11) 3437-3449
- 19 Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood 2007; 109 (8) 3161-3172
- 20 Shibata M, Kumar SR, Amar A , et al. Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation 2001; 103 (13) 1799-1805
- 21 Cheng T, Petraglia AL, Li Z , et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med 2006; 12 (11) 1278-1285
- 22 Gorbacheva L, Pinelis V, Ishiwata S, Strukova S, Reiser G. Activated protein C prevents glutamate- and thrombin-induced activation of nuclear factor-kappaB in cultured hippocampal neurons. Neuroscience 2010; 165 (4) 1138-1146
- 23 Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 2005; 105 (8) 3178-3184
- 24 Guo H, Liu D, Gelbard H , et al. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 2004; 41 (4) 563-572
- 25 Petraglia AL, Marky AH, Walker C, Thiyagarajan M, Zlokovic BV. Activated protein C is neuroprotective and mediates new blood vessel formation and neurogenesis after controlled cortical impact. Neurosurgery 2010; 66 (1) 165-171 , discussion 171–172
- 26 Manfioletti G, Brancolini C, Avanzi G, Schneider C. The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol 1993; 13 (8) 4976-4985
- 27 Prieto AL, Weber JL, Tracy S, Heeb MJ, Lai C. Gas6, a ligand for the receptor protein-tyrosine kinase Tyro-3, is widely expressed in the central nervous system. Brain Res 1999; 816 (2) 646-661
- 28 Tsaioun KI, Denisova NA, Obin M, Joseph J. Novel growth factor Gas6, phosphatidylserine and their age-related changes in the rat brain. Neurosci Res Commun 2000; 26 (2) 113-122
- 29 Allen MP, Zeng C, Schneider K , et al. Growth arrest-specific gene 6 (Gas6)/adhesion related kinase (Ark) signaling promotes gonadotropin-releasing hormone neuronal survival via extracellular signal-regulated kinase (ERK) and Akt. Mol Endocrinol 1999; 13 (2) 191-201
- 30 Funakoshi H, Yonemasu T, Nakano T, Matumoto K, Nakamura T. Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons. J Neurosci Res 2002; 68 (2) 150-160
- 31 Prieto AL, O'Dell S, Varnum B, Lai C. Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neurons. Neuroscience 2007; 150 (2) 319-334
- 32 Yagami T, Ueda K, Asakura K , et al. Effect of Gas6 on secretory phospholipase A(2)-IIA-induced apoptosis in cortical neurons. Brain Res 2003; 985 (2) 142-149
- 33 Shankar SL, O'Guin K, Cammer M , et al. The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway. J Neurosci 2003; 23 (10) 4208-4218
- 34 Shankar SL, O'Guin K, Kim M , et al. Gas6/Axl signaling activates the phosphatidylinositol 3-kinase/Akt1 survival pathway to protect oligodendrocytes from tumor necrosis factor alpha-induced apoptosis. J Neurosci 2006; 26 (21) 5638-5648
- 35 Binder MD, Cate HS, Prieto AL , et al. Gas6 deficiency increases oligodendrocyte loss and microglial activation in response to cuprizone-induced demyelination. J Neurosci 2008; 28 (20) 5195-5206
- 36 Binder MD, Xiao J, Kemper D, Ma GZ, Murray SS, Kilpatrick TJ. Gas6 increases myelination by oligodendrocytes and its deficiency delays recovery following cuprizone-induced demyelination. PLoS ONE 2011; 6 (3) e17727
- 37 Tsiperson V, Li X, Schwartz GJ, Raine CS, Shafit-Zagardo B. GAS6 enhances repair following cuprizone-induced demyelination. PLoS ONE 2010; 5 (12) e15748
- 38 Castoldi E, Hackeng TM. Regulation of coagulation by protein S. Curr Opin Hematol 2008; 15 (5) 529-536
- 39 Stitt TN, Conn G, Gore M , et al. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases. Cell 1995; 80 (4) 661-670
- 40 Phillips DJ, Greengard JS, Fernandez JA , et al. Protein S, an antithrombotic factor, is synthesized and released by neural tumor cells. J Neurochem 1993; 61 (1) 344-347
- 41 Liu D, Guo H, Griffin JH, Fernández JA, Zlokovic BV. Protein S confers neuronal protection during ischemic/hypoxic injury in mice. Circulation 2003; 107 (13) 1791-1796
- 42 Zhong Z, Wang Y, Guo H , et al. Protein S protects neurons from excitotoxic injury by activating the TAM receptor Tyro3-phosphatidylinositol 3-kinase-Akt pathway through its sex hormone-binding globulin-like region. J Neurosci 2010; 30 (46) 15521-15534
- 43 Zhu D, Wang Y, Singh I , et al. Protein S controls hypoxic/ischemic blood-brain barrier disruption through the TAM receptor Tyro3 and sphingosine 1-phosphate receptor. Blood 2010; 115 (23) 4963-4972
- 44 Gely-Pernot A, Coronas V, Harnois T , et al. An endogenous vitamin K-dependent mechanism regulates cell proliferation in the brain subventricular stem cell niche. Stem Cells 2012; 30 (4) 719-731
- 45 Bartke N, Hannun YA. Bioactive sphingolipids: metabolism and function. J Lipid Res 2009; 50 (Suppl): S91-S96
- 46 Zeidan YH, Hannun YA. Translational aspects of sphingolipid metabolism. Trends Mol Med 2007; 13 (8) 327-336
- 47 Cutler RG, Kelly J, Storie K , et al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci U S A 2004; 101 (7) 2070-2075
- 48 Jana A, Hogan EL, Pahan K. Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death. J Neurol Sci 2009; 278 (1–2) 5-15
- 49 Posse de Chaves E, Sipione S. Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction. FEBS Lett 2010; 584 (9) 1748-1759
- 50 Lev M, Milford AF. Vitamin K stimulation of sphingolipid synthesis. Biochem Biophys Res Commun 1971; 45 (2) 358-362
- 51 Lev M, Milford AF. Effect of vitamin K depletion and restoration on sphingolipid metabolism in Bacteroides melaninogenicus. J Lipid Res 1972; 13 (3) 364-370
- 52 Lev M, Milford AF. The 3-ketodihydrosphingosine synthetase of Bacteroides melaninogenicus: induction by vitamin K. Arch Biochem Biophys 1973; 157 (2) 500-508
- 53 Sundaram KS, Lev M. Warfarin administration reduces synthesis of sulfatides and other sphingolipids in mouse brain. J Lipid Res 1988; 29 (11) 1475-1479
- 54 Sundaram KS, Lev M. Regulation of sulfotransferase activity by vitamin K in mouse brain. Arch Biochem Biophys 1990; 277 (1) 109-113
- 55 Sundaram KS, Fan JH, Engelke JA, Foley AL, Suttie JW, Lev M. Vitamin K status influences brain sulfatide metabolism in young mice and rats. J Nutr 1996; 126 (11) 2746-2751
- 56 Crivello NA, Casseus SL, Peterson JW, Smith DE, Booth SL. Age- and brain region-specific effects of dietary vitamin K on myelin sulfatides. J Nutr Biochem 2010; 21 (11) 1083-1088
- 57 He X, Huang Y, Li B, Gong CX, Schuchman EH. Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol Aging 2010; 31 (3) 398-408
- 58 Ohmi Y, Tajima O, Ohkawa Y , et al. Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues. Proc Natl Acad Sci U S A 2009; 106 (52) 22405-22410
- 59 Tsang CK, Kamei Y. Novel effect of vitamin K(1) (phylloquinone) and vitamin K(2) (menaquinone) on promoting nerve growth factor-mediated neurite outgrowth from PC12D cells. Neurosci Lett 2002; 323 (1) 9-12
- 60 Nakajima M, Furukawa S, Hayashi K, Yamada A, Kawashima T, Hayashi Y. Age-dependent survival-promoting activity of vitamin K on cultured CNS neurons. Brain Res Dev Brain Res 1993; 73 (1) 17-23
- 61 Li J, Lin JC, Wang H , et al. Novel role of vitamin k in preventing oxidative injury to developing oligodendrocytes and neurons. J Neurosci 2003; 23 (13) 5816-5826
- 62 Li J, Wang H, Rosenberg PA. Vitamin K prevents oxidative cell death by inhibiting activation of 12-lipoxygenase in developing oligodendrocytes. J Neurosci Res 2009; 87 (9) 1997-2005
- 63 Sakaue M, Mori N, Okazaki M , et al. Vitamin K has the potential to protect neurons from methylmercury-induced cell death in vitro. J Neurosci Res 2011; 89 (7) 1052-1058
- 64 Reddi K, Henderson B, Meghji S , et al. Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Cytokine 1995; 7 (3) 287-290
- 65 Koshihara Y, Hoshi K, Shiraki M. Vitamin K2 (menatetrenone) inhibits prostaglandin synthesis in cultured human osteoblast-like periosteal cells by inhibiting prostaglandin H synthase activity. Biochem Pharmacol 1993; 46 (8) 1355-1362
- 66 Moriya M, Nakatsuji Y, Okuno T, Hamasaki T, Sawada M, Sakoda S. Vitamin K2 ameliorates experimental autoimmune encephalomyelitis in Lewis rats. J Neuroimmunol 2005; 170 (1–2) 11-20
- 67 Ohsaki Y, Shirakawa H, Hiwatashi K, Furukawa Y, Mizutani T, Komai M. Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci Biotechnol Biochem 2006; 70 (4) 926-932
- 68 Ohsaki Y, Shirakawa H, Miura A , et al. Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor κB through the repression of IKKα/β phosphorylation. J Nutr Biochem 2010; 21 (11) 1120-1126
- 69 Shea MK, Booth SL, Massaro JM , et al. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am J Epidemiol 2008; 167 (3) 313-320
- 70 Shea MK, Dallal GE, Dawson-Hughes B , et al. Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am J Clin Nutr 2008; 88 (2) 356-363
- 71 Cocchetto DM, Miller DB, Miller LL, Bjornsson TD. Behavioral perturbations in the vitamin K-deficient rat. Physiol Behav 1985; 34 (5) 727-734
- 72 Pauli RM. Mechanism of bone and cartilage maldevelopment in the warfarin embryopathy. Pathol Immunopathol Res 1988; 7 (1–2) 107-112
- 73 Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68 (1) 122-140
- 74 Presse N, Shatenstein B, Kergoat MJ, Ferland G. Low vitamin K intakes in community-dwelling elders at an early stage of Alzheimer's disease. J Am Diet Assoc 2008; 108 (12) 2095-2099
- 75 Presse N, Belleville S, Gaudreau P , et al. Vitamin K status and cognitive function in healthy older adults. Neurobiol Aging 2013; 34 (12) 2777-2783