Abstract
The blood-brain barrier (BBB) is a physical and biochemical barrier that maintains cerebral homeostasis. BBB dysfunction in an ischemic stroke, results in brain injury and subsequent neurological impairment. The aim of this study was to determine the possible protective effects of 1, 25-dihydroxyvitamin D3 [1, 25(OH)2D3, 1, 25-D3, vit D] on BBB dysfunction, at the early stages of an acute ischemic brain injury. We analyzed the effects of 1, 25-D3 on BBB integrity in terms of histopathological changes, the neurological deficit, infarct size and the expression of brain derived neurotrophic factor (BDNF), in a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model. BBB permeability and the expression of permeability-related proteins in the brain were also evaluated by Evans blue (EB) staining and Western blotting respectively. To determine the possible mechanism underlying the role of 1, 25-D3 in BBB maintenance, after MCAO/R, the rats were treated with the specific peroxisome proliferator-activated receptor gamma (PPARγ) inhibitor GW9662. Supplementation with 1, 25-D3 markedly improved the neurological scores of the rats, decreased the infarct volume, prevented neuronal deformation and upregulated the expression of the tight junction (TJ) and BDNF proteins in their brains. Furthermore, it activated PPARγ but downregulated neuro-inflammatory cytokines such as nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α), after MCAO/R. Taken together, 1, 25-D3 protects against cerebral ischemia by maintaining BBB permeability, upregulating the level of BDNF and inhibiting PPARγ-mediated neuro-inflammation.
Highlights
Stroke is a common neurological disorder accompanied by a high risk of disability and mortality (Ludewig et al, 2013; Deng et al, 2016)
Pre-treatment with 1, 25-D3 significantly reduced Evans blue (EB) extravasation (Figure 4C, ∗∗∗P < 0.001, ###P < 0.001, &&P < 0.01), while GW9662 reversed the effects of 1, 25-D3 on blood-brain barrier (BBB) permeability. These results indicated that 1, 25-D3 protected middle cerebral artery occlusion/reperfusion (MCAO/R) rats from the ischemic damage on BBB permeability and this effect was abrogated by GW9662
We investigated the effects of 1, 25-D3 on reperfusion-induced BBB disruption in a MCAO/R rat model and found that pre-treatment with this 1, 25-D3 protected the rats from neurological deficits, reduced the infarct volume and prevented neuronal injury after MCAO/R
Summary
Stroke is a common neurological disorder accompanied by a high risk of disability and mortality (Ludewig et al, 2013; Deng et al, 2016). Ischemic stroke can disrupt the blood-brain barrier (BBB), and induce brain edema, inflammation and neuronal injury, all of which cause severe structural and functional deterioration The recombinant tissue-type plasminogen activator (rt-PA) has a certain therapeutic effect on ischemic stroke as a thrombolytic agent, its clinical use is limited due to the narrow therapeutic window and its adverse effects It is necessary to identify novel drugs against ischemic stroke and elucidate their underlying mechanisms of action
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