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. 2022 Oct 27;11(11):2120. doi: 10.3390/antiox11112120

Table 2.

Effects of vitamin D in experimental stroke models—in vivo studies.

Model Animal Treatment Effects of Vitamin D Reference
Hypoxia ischemia (HI) rat model Hypothermia treatment + NAC (50 mg/kg) + 1,25-(OH)2D3 (0.1 μg/kg/)/daily for 2 weeks
↑motor skills
↓anxiety
↑spatial learning
[103]
Rat model of perinatal asphyxia in 7-day-old pups 1,25(OH)2D3 (2 μg/kg, i.p., single dose)/30 min after the insult or for 6 consecutive days ↓brain damage [98]

MCAO/R rat model of I/R injury


1,25(OH)2D3 (1 μg/kg i.p.)/day/8 days before ischemia.
DHA (250 mg/mL, from tail vein/30 min before MCAO/R
↓MDA
↑GSH, SOD activity in cortex and corpus striatum in 1,25(OH)2D3 + DHA group
[104]
MCA ligation model in rat 1,25(OH)2D3, 1 μg/kg/day, i.p., 4 or 8 days ↓the amount of infarction in the cortex,
↑GDNF levels
[105]
MCAO/R model in C57BL6 mice 1,25(OH)2D3 (100 ng/kg, i.p./day/5 day prior to stroke ↓infarct volume
↓pro-inflammatory mediators IL-6, IL-1β, IL-23a, TGF-β and NADPH oxidase-2
[106]
Spinal cord I/R injury in rabbit 1,25(OH)2D3 (0.5 μg/kg, i.p./7 days before I/R) ↓MDA, myeloperoxidase, xanthine oxidase activities, caspase-3 level,
↑catalase level, histopathological, ultrastructural, and neurological scores
[107]
BCAO model in Mongolian gerbils 1,25(OH)2D3 1 μg/kg, i.p./day/7 days prior to ischemia. ↓MMP-9
↓lipid peroxidation
↓superoxide anion production
↑VDR expression
[108]
GCI model in rat 1,25(OH)2D3 (1 μg/kg, i.p.)/30 min, 12 and 24 h after the GCI insult and PD98059 (5 μg, through the tail vein)/30 min prior to the insult ↓brain edema,
↑neurological function,
↑ERK 1/2 pathway activation,
↓neuronal apoptosis
[109]
GCI model in rat

1,25(OH)2D3 (1 μg/kg, i.p.)/30 min, 12 and 24 h after the GCI insult and PD98059 (5 μg, through the tail vein)/30 min prior to the insult

↑the spatial learning and memory
↑neurological function
↓brain edema,
↓morphological defects in the CA1 area of the hippocampus
↓apoptosis
↑ VDR expression
↑ERK 1/2 pathway activation—PD98059 reversed the anti-apoptotic effect of 1,25(OH)2D3
[110]
MCAO model in rat 1,25(OH)2D3, 7 days prior to stroke induction ↓lesion volume,
ischemic neurobehavioral deficits,
regulation of the glutamate receptor expression and CYP46A1 genes
[111]
MCAO model in rat 1,25(OH)2D3 i.p., (a single dose of 2 μg/kg, immediately following ischemia) and subchronically (2 μg/kg on 6 consecutive days). ↓infarct volumes 7 days following reperfusion,
↑NR3A and CREB activity in the hippocampal neurons, protection of the brain from I/R injury through the NR3A-MEK/ERK1/2-CREB pathway
[112]
Focal cortical ischemia (photothrombosis model) in rat Lesioned rats were injected i.p. one hour after injury with either 1 μg 1,25(OH)2D3/kg or 7 μg 17β-estradiol/kg or a combination of both steroids ↓HSP-27 within the infracted cerebral cortex [114]
tMCAO model in rat Progesterone (8 mg/kg), 1,25(OH)2D3 (1 μg/kg body weight/day) alone or in a combination, 5 min. i.p. prior to reperfusion followed by daily s.c. injections for 6 days. ↓motor deficits, infarct reduction, ↑BDNF, TrkB and p-ERK1/2 expression,
↓apoptosis (↑Bcl-2, ↓caspase-3)
↓IL-6 and p-NF-κB
↑HO-1
[100]
Focal cortical ischemia (photothrombosis model) in rat
Postlesional treatment with 1,25(OH)2D3 (4 μg/kg i.p.) ↑glial HO-1
↓GFAP
[115]
Focal cortical ischemia (photothrombosis model) in rat 1,25(OH)2D3 (4 μg/kg i.p.) no significant differences between 1,25(OH)2D3-treated and solvent-treated lesioned rats in neuronal COX-2 expression
[116]
MCAO model in female rat Vit. D deficiency (VDD) diet for 8 weeks before MCAO;

10 μg/kg 1,25(OH)2D3, 4 h after MCAO and every 24 h thereafter for 5 days
VDD diet effects: ↑cortical and striatal infarct volumes,
↑severe poststroke behavioral impairment
↓IGF-I in plasma and the ischemic hemisphere,
↓IL-1α, IL-1β, IL-2, IL-4, IFN-γ, and IL-10 expression in ischemic brain tissue,
↑IL-6
Acute 1,25(OH)2D3 treatment did not improve infarct volume or behavioral performance
[117]
Hypoxia/reoxygenation (H/R) model in bEnd.3 cells 1,25(OH)2D3 (5–200 nmol/L)/24 h before H/R, continued throughout the H/R period ↑BBB function,
zonula occludin-1, claudin-5, and occludin,
↓NF-κB
↓MMP-9
[118]
MCAO model in rat 1,25(OH)2D3 i.p. one group—12 μg/kg immediately after the ischemia period (60 min) second group—2 μg/kg after MCAO and over the next 5 days ↓brain infarction volume, brain edema formation
↑BBB function
↑antioxidant enzyme activities
↓cell apoptosis
↑BDNF immunoreactivity
[119]
MCAO rat model Vit. D3, 1000 IU/kg/day
through gavage/14 days
↓the size of cerebral infarction,
↑cerebral perfusion
in the ischemic area
↑levels of vascular growth-related factor
↑micro-vessel density after cerebral infarction and
↑the proliferation of
vascular endothelial cells in the ischemic cortex

↑Shh signaling in the ischemic cortex
[120]
MCAO rat model Vit. D3 100 ng/kg i.v., vit. D3 nanoemulsion i.v. and intranasal (a mean size range of 49.29 ± 10.28 nm, equivalent to 100 ng/kg vit. D3 ↑BBB permeation, deposition, and efficacy of vit. D3-nanoemulsion through the intranasal route in comparison i.v. vit. D3 or vit. D3 nanoemulsion
[121]
MCAO model in C57BL6 mice 1,25(OH)2D3 (100 ng/kg, i.p./day/5 days before MCAO ↓the volume of cerebral infarction
↓IL-6, IL-1β, IL-23a, TGF-β, Gp91phox
[106]
MCAO combined with CUMS in mice Vit. D3 (6–50 μg/kg), icv/4 weeks ↓motor dysfunction and depression-like behaviors
↑VDR expression and BDNF
[15]
tMCAO model in rat Calcitriol 1 µg/kg, i.p., 7 consecutive days before experimental induction of stroke ↓infarction volume ↓neurological deficits in brain,
↓MDA and NO levels ↑TAC level,
↑HO-1 and Nrf2 protein and mRNA
[124]

↑: increase; ↓: decrease; 1,25(OH)2D3: calcitriol; BBB: blood brain barrier; BCAO: bilateral common carotid occlusion; BDNF: brain derived neurotrophic factor; bEnd.3: an immortalized mouse brain endothelial cell line; COX-2: cyclooxygenase 2; CUMS: chronic unpredicted mild stress; DHA: dehydroascorbic acid; ERK1/2: extracellular signal-regulated kinase 1 and 2; GCI: global cerebral ischemia; GDNF: glial cell-derived neurotrophic factor; GFAP: glial fibrillary acidic protein; Gp91phox: the NOX family of NADPH oxidases; GSH: glutathione; HO-1: heme oxygenase; i.p.: intraperitoneal; I/R: ischemia/reperfusion; MCA: middle cerebral arterial; MCAO/R: middle cerebral artery occlusion/reperfusion model; MDA: malondialdehyde; MEK: mitogen-activated protein kinase; MMP9: matrix metalloproteinases 9; NAC: N-acetylcysteine; NO: nitric oxide; NR3A: NMDA receptor subunit 3A; Nrf2: nuclear factor erythroid 2-related factor 2; p-CREB-Ca2+: response element binding protein; PD98059: p-ERK1/2 inhibitor; Shh: sonic hedgehog pathway; SOD: superoxide dismutase; TAC: total antioxidant capacity; TrkB: tyrosine receptor kinase B; VDR: vitamin D receptor.