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

• DOI: 10.1007/s12017-018-8484-z
• Publication Date: 2018-02-23T14:16:16Z
• 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
• Keywords: calcitriol; Male; interleukin 1beta; middle cerebral artery occlusion; nerve protein; immune response; regulatory T lymphocyte; retinoid related orphan receptor gamma; T-Lymphocyte Subsets; cytokine; animal; interleukin 23p19; Cholecalciferol; transforming growth factor beta; Th17 cell; sterile water; 0303 health sciences; alcohol; gamma delta T lymphocyte; Foxp3 protein; neuroprotective agent; Brain; Forkhead Transcription Factors; Infarction, Middle Cerebral Artery; Nuclear Receptor Subfamily 1, Group F, Member 3; reperfusion injury; 3. Good health; Neuroprotective Agents; priority journal; Neutrophil Infiltration; propylene glycol; forkhead transcription factor; Cytokines; Microglia; Inflammation Mediators; autacoid; colecalciferol; brain; animal experiment; transcription factor FOXP3; interleukin 6; 610; reduced nicotinamide adenine dinucleotide phosphate oxidase 2; immunocompetent cell; Nerve Tissue Proteins; Motor Activity; Article; animal tissue; 618; 03 medical and health sciences; male; Animals; brain infarction size; controlled study; lymphocyte count; protein expression; mouse; Inflammation; Original Paper; nonhuman; neutrophil count; Macrophages; disease association; antiinflammatory activity; vitamin supplementation; brain injury; brain ischemia; Mice, Inbred C57BL; Rorc protein; Gene Expression Regulation; inflammation; biosynthesis

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.