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Open Access 01-03-2018 | Original Paper

Vitamin D₃ Supplementation Reduces Subsequent Brain Injury and Inflammation Associated with Ischemic Stroke

Authors: Megan A. Evans, Hyun Ah Kim, Yeong Hann Ling, Sandy Uong, Antony Vinh, T. Michael De Silva, Thiruma V. Arumugam, Andrew N. Clarkson, Graeme R. Zosky, Grant R. Drummond, Brad R. S. Broughton, Christopher G. Sobey

Published in: NeuroMolecular Medicine | Issue 1/2018

Abstract

Acute inflammation can exacerbate brain injury after ischemic stroke. Beyond its well-characterized role in calcium metabolism, it is becoming increasingly appreciated that the active form of vitamin D, 1,25-dihydroxyvitamin D₃ (1,25-VitD₃), has potent immunomodulatory properties. Here, we aimed to determine whether 1,25-VitD₃ supplementation could reduce subsequent brain injury and associated inflammation after ischemic stroke. Male C57Bl6 mice were randomly assigned to be administered either 1,25-VitD₃ (100 ng/kg/day) or vehicle i.p. for 5 day prior to stroke. Stroke was induced via middle cerebral artery occlusion for 1 h followed by 23 h reperfusion. At 24 h post-stroke, we assessed infarct volume, functional deficit, expression of inflammatory mediators and numbers of infiltrating immune cells. Supplementation with 1,25-VitD₃ reduced infarct volume by 50% compared to vehicle. Expression of pro-inflammatory mediators IL-6, IL-1β, IL-23a, TGF-β and NADPH oxidase-2 was reduced in brains of mice that received 1,25-VitD₃ versus vehicle. Brain expression of the T regulatory cell marker, Foxp3, was higher in mice supplemented with 1,25-VitD₃ versus vehicle, while expression of the transcription factor, ROR-γ, was decreased, suggestive of a reduced Th17/γδ T cell response. Immunohistochemistry indicated that similar numbers of neutrophils and T cells were present in the ischemic hemispheres of 1,25-VitD₃- and vehicle-supplemented mice. At this early time point, there were also no differences in the impairment of motor function. These data indicate that prior administration of exogenous vitamin D, even to vitamin D-replete mice, can attenuate infarct development and exert acute anti-inflammatory actions in the ischemic and reperfused brain.

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Anrather, J., & Iadecola, C. (2016). Inflammation and stroke: An overview. Neurotherapeutics, 13(4), 661–670. https://doi.org/10.1007/s13311-016-0483-x.CrossRefPubMedPubMedCentral

Benakis, C., Brea, D., Caballero, S., Faraco, G., Moore, J., Murphy, M., et al. (2016). Commensal microbiota affects ischemic stroke outcome by regulating intestinal γδ T cells. Nature Medicine, 22(5), 516–523. https://doi.org/10.1038/nm.4068.CrossRefPubMedPubMedCentral

Benakis, C., Garcia-Bonilla, L., Iadecola, C., & Anrather, J. (2014). The role of microglia and myeloid immune cells in acute cerebral ischemia. Frontiers in Cellular Neuroscience, 8, 461. https://doi.org/10.3389/fncel.2014.00461.PubMed

Boontanrart, M., Hall, S. D., Spanier, J. A., Hayes, C. E., & Olson, J. K. (2016). Vitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism. Journal of Neuroimmunology, 292, 126–136. https://doi.org/10.1016/j.jneuroim.2016.01.015.CrossRefPubMed

Brewer, L. D., Thibault, V., Chen, K.-C., Langub, M. C., Landfield, P. W., & Porter, N. M. (2001). Vitamin D hormone confers neuroprotection in parallel with downregulation of L-Type calcium channel expression in hippocampal neurons. Journal of Neuroscience, 21(1), 98–108.PubMed

Cantorna, M. T., Hayes, C. E., & DeLuca, H. F. (1996). 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proceedings of the National Academy of Sciences, USA. https://doi.org/10.1073/pnas.93.15.7861.

Cantorna, M. T., Zhu, Y., Froicu, M., & Wittke, A. (2004). Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. American Journal of Clinical Nutrition, 80(6 Suppl), 1717s–1720s.CrossRefPubMed

Chang, J. H., Cha, H. R., Lee, D. S., Seo, K. Y., & Kweon, M. N. (2010a). 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H)17 cells to protect against experimental autoimmune encephalomyelitis. PLoS ONE, 5, e12925. https://doi.org/10.1371/journal.pone.0012925.CrossRefPubMedPubMedCentral

Chang, S. H., Chung, Y., & Dong, C. (2010b). Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. Journal of Biological Chemistry, 285(50), 38751–38755. https://doi.org/10.1074/jbc.C110.185777.CrossRefPubMedPubMedCentral

Chen, L., Cencioni, M. T., Angelini, D. F., Borsellino, G., Battistini, L., & Brosnan, C. F. (2005). Transcriptional profiling of γδ T cells identifies a role for vitamin D in the immunoregulation of the Vγ9 Vδ2 response to phosphate-containing ligands. The Journal of Immunology, 174(10), 6144–6152. https://doi.org/10.4049/jimmunol.174.10.6144.CrossRefPubMed

Chu, H. X., Broughton, B. R., Kim, H. A., Lee, S., Drummond, G. R., & Sobey, C. G. (2015). Evidence that Ly6C(hi) monocytes are protective in acute ischemic stroke by promoting M2 macrophage polarization. [Research Support, Non-U.S. Gov’t]. Stroke, 46(7), 1929–1937. https://doi.org/10.1161/strokeaha.115.009426.CrossRefPubMed

Daubail, B., Jacquin, A., Guilland, J. C., Hervieu, M., Osseby, G. V., Rouaud, O., et al. (2013). Serum 25-hydroxyvitamin D predicts severity and prognosis in stroke patients. European Journal of Neurology, 20(1), 57–61. https://doi.org/10.1111/j.1468-1331.2012.03758.x.CrossRefPubMed

De Silva, T. M., Brait, V. H., Drummond, G. R., Sobey, C. G., & Miller, A. A. (2011). Nox₂ oxidase activity accounts for the oxidative stress and vasomotor dysfunction in mouse cerebral arteries following ischemic stroke. PLoS ONE, 6(12), e28393. https://doi.org/10.1371/journal.pone.0028393.CrossRefPubMedPubMedCentral

Del Zoppo, G. J., Saver, J. L., Jauch, E. C., & Adams, H. P., Jr. (2009). Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. [Practice guideline]. Stroke, 40(8), 2945–2948. https://doi.org/10.1161/strokeaha.109.192535.CrossRefPubMedPubMedCentral

Dong, J., Wong, S. L., Lau, C. W., Lee, H. K., Ng, C. F., Zhang, L., et al. (2012). Calcitriol protects renovascular function in hypertension by down-regulating angiotensin II type 1 receptors and reducing oxidative stress. European Heart Journal, 33(23), 2980–2990. https://doi.org/10.1093/eurheartj/ehr459.CrossRefPubMed

Evans, M. A., Kim, H. A., De Silva, T. M., Arumugam, T. V., Clarkson, A. N., Drummond, G. R., et al. (2017). Diet-induced vitamin D deficiency has no effect on acute post-stroke outcomes in young male mice. Journal of Cerebral Blood Flow and Metabolism. https://doi.org/10.1177/0271678x17719208.

Evans, M. A., Lim, R., Kim, H. A., Chu, H. X., Gardiner-Mann, C. V., Taylor, K. W. E., et al. (2018). Acute or delayed systemic administration of human amnion epithelial cells improves outcomes in experimental stroke. Stroke. https://doi.org/10.1161/strokeaha.117.019136.PubMed

Eyles, D. W., Smith, S., Kinobe, R., Hewison, M., & McGrath, J. J. (2005). Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. Journal of Chemical Neuroanatomy, 29(1), 21–30. https://doi.org/10.1016/j.jchemneu.2004.08.006.CrossRefPubMed

Fu, J., Xue, R., Gu, J., Xiao, Y., Zhong, H., Pan, X., et al. (2013). Neuroprotective effect of calcitriol on ischemic/reperfusion injury through the NR3A/CREB pathways in the rat hippocampus. Mol Med Rep, 8(6), 1708–1714. https://doi.org/10.3892/mmr.2013.1734.CrossRefPubMed

Gelderblom, M., Leypoldt, F., Steinbach, K., Behrens, D., Choe, C. U., Siler, D. A., et al. (2009). Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke, 40(5), 1849–1857. https://doi.org/10.1161/strokeaha.108.534503.CrossRefPubMed

Gelderblom, M., Weymar, A., Bernreuther, C., Velden, J., Arunachalam, P., Steinbach, K., et al. (2012). Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood, 120(18), 3793–3802.CrossRefPubMed

Gorman, S., Judge, M. A., & Hart, P. H. (2010). Topical 1,25-dihydroxyvitamin D3 subverts the priming ability of draining lymph node dendritic cells. Immunology, 131(3), 415–425. https://doi.org/10.1111/j.1365-2567.2010.03315.x.CrossRefPubMedPubMedCentral

Gregori, S., Giarratana, N., Smiroldo, S., Uskokovic, M., & Adorini, L. (2002). A 1α,25-dihydroxyvitamin D analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes, 51(5), 1367–1374. https://doi.org/10.2337/diabetes.51.5.1367.CrossRefPubMed

Grishkan, I. V., Fairchild, A. N., Calabresi, P. A., & Gocke, A. R. (2013). 1,25-dihydroxyvitamin D3 selectively and reversibly impairs T helper-cell CNS localization. Proceedings of the National Academy of Sciences of the United States of America, 110(52), 21101–21106. https://doi.org/10.1073/pnas.1306072110.CrossRefPubMedPubMedCentral

Gu, L., Xiong, X., Zhang, H., Xu, B., Steinberg, G. K., & Zhao, H. (2012). Distinctive effects of T cell subsets in neuronal injury induced by cocultured splenocytes in vitro and by in vivo stroke in mice. Stroke, 43(7), 1941–1946.CrossRefPubMedPubMedCentral

Hart, P. H., Gorman, S., & Finlay-Jones, J. J. (2011). Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nature Reviews Immunology, 11(9), 584–596. https://doi.org/10.1038/nri3045.CrossRefPubMed

Holick, M. F. (2007). Vitamin D deficiency. New England Journal of Medicine, 357(3), 266–281. https://doi.org/10.1056/NEJMra070553.CrossRefPubMed

Hu, X., Li, P., Guo, Y., Wang, H., Leak, R. K., Chen, S., et al. (2012). Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke, 43(11), 3063–3070. https://doi.org/10.1161/STROKEAHA.112.659656.CrossRefPubMed

Jain, S. K., & Micinski, D. (2013). Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochemical and Biophysical Research Communications, 437(1), 7–11. https://doi.org/10.1016/j.bbrc.2013.06.004.CrossRefPubMedPubMedCentral

Joshi, S., Pantalena, L. C., Liu, X. K., Gaffen, S. L., Liu, H., Rohowsky-Kochan, C., et al. (2011). 1,25-Dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Molecular and Cellular Biology, 31(17), 3653–3669. https://doi.org/10.1128/MCB.05020-11.CrossRefPubMedPubMedCentral

Kleindorfer, D., Lindsell, C. J., Brass, L., Koroshetz, W., & Broderick, J. P. (2008). National US estimates of recombinant tissue plasminogen activator use: ICD-9 codes substantially underestimate. Stroke, 39(3), 924–928. https://doi.org/10.1161/STROKEAHA.107.490375.CrossRefPubMed

Korf, H., Wenes, M., Stijlemans, B., Takiishi, T., Robert, S., Miani, M., et al. (2012). 1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism. Immunobiology, 217(12), 1292–1300. https://doi.org/10.1016/j.imbio.2012.07.018.CrossRefPubMed

Landel, V., Millet, P., Baranger, K., Loriod, B., & Feron, F. (2016). Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer’s disease. Molecular Neurodegeneration, 11, 22. https://doi.org/10.1186/s13024-016-0087-2.CrossRefPubMedPubMedCentral

Langub, M. C., Herman, J. P., Malluche, H. H., & Koszewski, N. J. (2001). Evidence of functional vitamin D receptors in rat hippocampus. Neuroscience, 104(1), 49–56.CrossRefPubMed

Lee, S., Evans, M. A., Chu, H. X., Kim, H. A., Widdop, R. E., Drummond, G. R., et al. (2015). Effect of a selective Mas receptor agonist in cerebral ischemia in vitro and in vivo. PLoS ONE, 10(11), e0142087. https://doi.org/10.1371/journal.pone.0142087.CrossRefPubMedPubMedCentral

Lee, J. H., O’Keefe, J. H., Bell, D., Hensrud, D. D., & Holick, M. F. (2008). Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? Journal of the American College of Cardiology, 52(24), 1949–1956. https://doi.org/10.1016/j.jacc.2008.08.050.CrossRefPubMed

Liesz, A., Suri-Payer, E., Veltkamp, C., Doerr, H., Sommer, C., Rivest, S., et al. (2009). Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nature Medicine, 15(2), 192–199. https://doi.org/10.1038/nm.1927.CrossRefPubMed

Liu, P. T., Stenger, S., Li, H., Wenzel, L., Tan, B. H., Krutzik, S. R., et al. (2006). Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science, 311(5768), 1770–1773. https://doi.org/10.1126/science.1123933.CrossRefPubMed

Lugg, S. T., Howells, P. A., & Thickett, D. R. (2015). Optimal vitamin D supplementation levels for cardiovascular disease protection. Disease Markers, 2015, 1–10. https://doi.org/10.1155/2015/864370.CrossRef

Luo, W., Hershberger, P. A., Trump, D. L., & Johnson, C. S. (2013). 24-Hydroxylase in cancer: impact on vitamin D-based anticancer therapeutics. Journal of Steroid Biochemistry and Molecular Biology, 136, 252–257. https://doi.org/10.1016/j.jsbmb.2012.09.031.CrossRefPubMed

Martorell, S., Hueso, L., Gonzalez-Navarro, H., Collado, A., Sanz, M. J., & Piqueras, L. (2016). Vitamin D receptor activation reduces angiotensin-II-induced dissecting abdominal aortic aneurysm in apolipoprotein E-knockout mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 36(8), 1587–1597. https://doi.org/10.1161/ATVBAHA.116.307530.CrossRefPubMed

Mattner, F., Smiroldo, S., Galbiati, F., Muller, M., Di Lucia, P., Poliani, P. L., et al. (2000). Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a non-hypercalcemic analogue of 1,25-dihydroxyvitamin D3. European Journal of Immunology, 30(2), 498–508. https://doi.org/10.1002/1521-4141(200002)30:2<498::AID-IMMU498>3.0.CO;2-Q.CrossRefPubMed

Merke, J., Milde, P., Lewicka, S., Hugel, U., Klaus, G., Mangelsdorf, D. J., et al. (1989). Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. Journal of Clinical Investigation, 83(6), 1903–1915. https://doi.org/10.1172/jci114097.CrossRefPubMedPubMedCentral

Mozaffarian, D., Benjamin, E. J., Go, A. S., Arnett, D. K., Blaha, M. J., Cushman, M., et al. (2016). Heart disease and stroke statistics-2016 update: A report from the american heart association. Circulation, 133(4), e38–e360. https://doi.org/10.1161/CIR.0000000000000350.CrossRefPubMed

Muthian, G., Raikwar, H. P., Rajasingh, J., & Bright, J. J. (2006). 1,25 Dihydroxyvitamin-D3 modulates JAK–STAT pathway in IL-12/IFNγ axis leading to Th1 response in experimental allergic encephalomyelitis. Journal of Neuroscience Research, 83(7), 1299–1309. https://doi.org/10.1002/jnr.20826.CrossRefPubMed

Nashold, F. E., Nelson, C. D., Brown, L. M., & Hayes, C. E. (2013). One calcitriol dose transiently increases Helios + FoxP3 + T cells and ameliorates autoimmune demyelinating disease. Journal of Neuroimmunology, 263(1–2), 64–74. https://doi.org/10.1016/j.jneuroim.2013.07.016.CrossRefPubMed

Naveilhan, P., Neveu, I., Wion, D., & Brachet, P. (1996). 1,25-Dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. NeuroReport, 7(13), 2171–2175.CrossRefPubMed

Neveu, I., Naveilhan, P., Jehan, Fdr, Baudet, C., Wion, D., De Luca, H. F., et al. (1994). 1,25-Dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in primary cultures of glial cells. Molecular Brain Research, 24(1–4), 70–76. https://doi.org/10.1016/0169-328X(94)90119-8.CrossRefPubMed

Oermann, E., Bidmon, H. J., Witte, O. W., & Zilles, K. (2004). Effects of 1alpha,25 dihydroxyvitamin D3 on the expression of HO-1 and GFAP in glial cells of the photothrombotically lesioned cerebral cortex. Journal of Chemical Neuroanatomy, 28(4), 225–238. https://doi.org/10.1016/j.jchemneu.2004.07.003.CrossRefPubMed

Overbergh, L., Decallonne, B., Valckx, D., Verstuyf, A., Depovere, J., Laureys, J., et al. (2000). Identification and immune regulation of 25-hydroxyvitamin D-1-α-hydroxylase in murine macrophages. Clinical and Experimental Immunology, 120(1), 139–146. https://doi.org/10.1046/j.1365-2249.2000.01204.x.CrossRefPubMedPubMedCentral

Park, K.-Y., Chung, P.-W., Kim, Y. B., Moon, H.-S., Suh, B.-C., Won, Y. S., et al. (2015). Serum vitamin D status as a predictor of prognosis in patients with acute ischemic stroke. Cerebrovascular Diseases, 40(1–2), 73–80. https://doi.org/10.1159/000434691.CrossRefPubMed

Pedersen, L. B., Nashold, F. E., Spach, K. M., & Hayes, C. E. (2007). 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. Journal of Neuroscience Research, 85(11), 2480–2490. https://doi.org/10.1002/jnr.21382.CrossRefPubMed

Penna, G., Amuchastegui, S., Giarratana, N., Daniel, K. C., Vulcano, M., Sozzani, S., et al. (2007). 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. Journal of Immunology, 178(1), 145–153.CrossRef

Provvedini, D. M., Tsoukas, C. D., Deftos, L. J., & Manolagas, S. C. (1983). 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science, 221(4616), 1181–1183.CrossRefPubMed

Reeves, M. J., Arora, S., Broderick, J. P., Frankel, M., Heinrich, J. P., Hickenbottom, S., et al. (2005). Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke, 36(6), 1232–1240. https://doi.org/10.1161/01.STR.0000165902.18021.5b.CrossRefPubMed

Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P., & Yamaguchi, T. (2009). Regulatory T cells: how do they suppress immune responses? International Immunology, 21(10), 1105–1111. https://doi.org/10.1093/intimm/dxp095.CrossRefPubMed

Schedel, M., Jia, Y., Michel, S., Takeda, K., Domenico, J., Joetham, A., et al. (2016). 1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter. Nature Communication, 7, 10213. https://doi.org/10.1038/ncomms10213.CrossRef

Shichita, T., Sugiyama, Y., Ooboshi, H., Sugimori, H., Nakagawa, R., Takada, I., et al. (2009). Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nature Medicine, 15(8), 946–950. https://doi.org/10.1038/nm.1999.CrossRefPubMed

Sloka, S., Silva, C., Wang, J., & Yong, V. W. (2011). Predominance of Th2 polarization by vitamin D through a STAT6-dependent mechanism. Journal of Neuroinflammation, 8(1), 56. https://doi.org/10.1186/1742-2094-8-56.CrossRefPubMedPubMedCentral

Sotirchos, E. S., Bhargava, P., Eckstein, C., Van Haren, K., Baynes, M., Ntranos, A., et al. (2016). Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology, 86(4), 382–390. https://doi.org/10.1212/wnl.0000000000002316.CrossRefPubMedPubMedCentral

Spanier, J. A., Nashold, F. E., Olson, J. K., & Hayes, C. E. (2012). The Ifng gene is essential for Vdr gene expression and vitamin D(3)-mediated reduction of the pathogenic T cell burden in the central nervous system in experimental autoimmune encephalomyelitis, a multiple sclerosis model. Journal of Immunology, 189(6), 3188–3197. https://doi.org/10.4049/jimmunol.1102925.CrossRef

Takeda, M., Yamashita, T., Sasaki, N., Nakajima, K., Kita, T., Shinohara, M., et al. (2010). Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(12), 2495–2503. https://doi.org/10.1161/atvbaha.110.215459.CrossRefPubMed

Taniura, H., Ito, M., Sanada, N., Kuramoto, N., Ohno, Y., Nakamichi, N., et al. (2006). Chronic vitamin D3 treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mRNA expression in cultured rat cortical neurons. Journal of Neuroscience Research, 83(7), 1179–1189. https://doi.org/10.1002/jnr.20824.CrossRefPubMed

Taylor, A., Verhagen, J., Blaser, K., Akdis, M., & Akdis, C. A. (2006). Mechanisms of immune suppression by interleukin-10 and transforming growth factor-β: the role of T regulatory cells. Immunology, 117(4), 433–442. https://doi.org/10.1111/j.1365-2567.2006.02321.x.CrossRefPubMedPubMedCentral

Tu, W. J., Zhao, S. J., Xu, D. J., & Chen, H. (2014). Serum 25-hydroxyvitamin D predicts the short-term outcomes of Chinese patients with acute ischaemic stroke. Clinical Science (London, England: 1979), 126(5), 339–346. https://doi.org/10.1042/cs20130284.CrossRef

Turetsky, A., Goddeau, R. P., Jr., & Henninger, N. (2015). Low serum vitamin D is independently associated with larger lesion volumes after ischemic stroke. Journal of Stroke and Cerebrovascular Diseases, 24(7), 1555–1563. https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.03.051.CrossRefPubMed

Vantourout, P., & Hayday, A. (2013). Six-of-the-best: unique contributions of [gamma][delta] T cells to immunology. Nature Reviews: Immunology, 13(2), 88–100. https://doi.org/10.1038/nri3384.PubMedPubMedCentral

Verma, R., & Kim, J. Y. (2016). 1,25-Dihydroxyvitamin D3 facilitates M2 polarization and upregulates TLR10 expression on human microglial cells. Neuroimmunomodulation, 23(2), 75–80. https://doi.org/10.1159/000444300.CrossRefPubMed

von Essen, M. R., Kongsbak, M., Schjerling, P., Olgaard, K., Odum, N., & Geisler, C. (2010). Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nature Immunology, 11(4), 344–349. https://doi.org/10.1038/ni.1851.CrossRef

Wang, Y., Ji, H., Tong, Y., & Zhang, Z. B. (2014). Prognostic value of serum 25-hydroxyvitamin D in patients with stroke. Neurochemical Research, 39(7), 1332–1337. https://doi.org/10.1007/s11064-014-1316-0.CrossRefPubMed

Won, S., Sayeed, I., Peterson, B. L., Wali, B., Kahn, J. S., & Stein, D. G. (2015). Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways. PLoS ONE, 10(3), e0122821. https://doi.org/10.1371/journal.pone.0122821.CrossRefPubMedPubMedCentral

Wong, M. S., Leisegang, M. S., Kruse, C., Vogel, J., Schurmann, C., Dehne, N., et al. (2014). Vitamin D promotes vascular regeneration. Circulation, 130(12), 976–986. https://doi.org/10.1161/CIRCULATIONAHA.114.010650.CrossRefPubMed

Yang, L., Brozovic, S., Xu, J., Long, Y., Kralik, P. M., Waigel, S., et al. (2011). Inflammatory gene expression in OVE26 diabetic kidney during the development of nephropathy. Nephron Experimental Nephrology, 119(1), e8–e20.CrossRefPubMed

Yao, T., Ying, X., Zhao, Y., Yuan, A., He, Q., Tong, H., et al. (2015). Vitamin D receptor activation protects against myocardial reperfusion injury through inhibition of apoptosis and modulation of autophagy. Antioxidants & Redox Signaling, 22(8), 633–650. https://doi.org/10.1089/ars.2014.5887.CrossRef

Yilmaz, G., Arumugam, T. V., Stokes, K. Y., & Granger, D. N. (2006). Role of T lymphocytes and interferon-gamma in ischemic stroke. Circulation, 113(17), 2105–2112.CrossRefPubMed

Zeitelhofer, M., Adzemovic, M. Z., Gomez-Cabrero, D., Bergman, P., Hochmeister, S., N’Diaye, M., et al. (2017). Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1615783114.PubMedPubMedCentral

Zhang, Y., Leung, D. Y., Richers, B. N., Liu, Y., Remigio, L. K., Riches, D. W., et al. (2012). Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. Journal of Immunology, 188(5), 2127–2135. https://doi.org/10.4049/jimmunol.1102412.CrossRef

Title: Vitamin D3 Supplementation Reduces Subsequent Brain Injury and Inflammation Associated with Ischemic Stroke
Authors: Megan A. Evans
Hyun Ah Kim
Yeong Hann Ling
Sandy Uong
Antony Vinh
T. Michael De Silva
Thiruma V. Arumugam
Andrew N. Clarkson
Graeme R. Zosky
Grant R. Drummond
Brad R. S. Broughton
Christopher G. Sobey
Publication date: 01-03-2018
Publisher: Springer US
Published in: NeuroMolecular Medicine / Issue 1/2018
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-018-8484-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Vitamin D₃ Supplementation Reduces Subsequent Brain Injury and Inflammation Associated with Ischemic Stroke

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At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

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Differential Binding of Human ApoE Isoforms to Insulin Receptor is Associated with Aberrant Insulin Signaling in AD Brain Samples

Combination Therapy with Low-Dose IVIG and a C1-esterase Inhibitor Ameliorates Brain Damage and Functional Deficits in Experimental Ischemic Stroke

Cardiovascular Autonomic Dysfunction: Link Between Multiple Sclerosis Osteoporosis and Neurodegeneration

Genetics and Treatment Response in Parkinson’s Disease: An Update on Pharmacogenetic Studies

Correction of Huntington’s Disease Phenotype by Genistein-Induced Autophagy in the Cellular Model

Inhibition of GSK-3beta Signaling Pathway Rescues Ketamine-Induced Neurotoxicity in Neural Stem Cell-Derived Neurons