Abstract
BackgroundCerebral oedema is closely related to the permeability of blood–brain barrier, vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) all of which are important blood–brain barrier (BBB) permeability regulatory factors. Zonula occludens 1 (ZO-1) and claudin-5 are also the key components of BBB. Hypertonic saline is widely used to alleviate cerebral oedema. This study aimed to explore the possible mechanisms underlying hypertonic saline that ameliorates cerebral oedema effectively.MethodsMiddle cerebral artery occlusion (MCAO) model in Sprague-Dawley (SD) rats and of oxygen–glucose deprivation model in primary astrocytes were used in this study. The brain water content (BWC) was used to assess the effect of 10 % HS on cerebral oedema. The assessment of Evans blue (EB) extravasation was performed to evaluate the protective effect of 10 % HS on blood–brain barrier. The quantification of VEGF, VEGFR2, ZO-1 and claudin-5 was used to illustrate the mechanism of 10 % HS ameliorating cerebral oedema.ResultsBWC was analysed by wet-to-dry ratios in the ischemic hemisphere of SD rats; it was significantly decreased after 10 % HS treatment (P < 0.05). We also investigated the blood–brain barrier protective effect by 10 % HS which reduced EB extravasation effectively in the peri-ischemic brain tissue. In parallel to the above notably at 24 h following MCAO, mRNA and protein expression of VEGF and VEGFR2 in the peri-ischemic brain tissue was down-regulated after 10 % HS treatment (P < 0.05). Along with this, in vitro studies showed increased VEGF and VEGFR2 mRNA and protein expression in primary astrocytes under hypoxic condition (P < 0.05), but it was suppressed after HS treatment (P < 0.05). In addition, HS inhibited the down-regulation of ZO-1, claudin-5 effectively.ConclusionsThe results suggest that 10 % HS could alleviate cerebral oedema possibly through reducing the ischemia induced BBB permeability as a consequence of inhibiting VEGF–VEGFR2-mediated down-regulation of ZO-1, claudin-5.
Highlights
Cerebral oedema is closely related to the permeability of blood–brain barrier, vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) all of which are important blood–brain barrier (BBB) permeability regulatory factors
The group of Schwab has been reported that 10 % hypertonic saline (HS) effective in reducing the common cerebral oedema, and for cases that failed with mannitol treatment [5]
Ipsilateral ischemic hemispheric brain water content (BWC) The Longa scores showed that no significant difference between ischemia group and 10 % HS group (Fig. 1A; ns: P > 0.05)
Summary
Cerebral oedema is closely related to the permeability of blood–brain barrier, vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) all of which are important blood–brain barrier (BBB) permeability regulatory factors. Hypertonic saline is widely used to alleviate cerebral oedema. The development of cerebral oedema remains the most significant predictor of treatment outcome. If it is not treated timely and with an effective strategy, it could be life-threatening due to formation of cerebral hernia. To this end, osmotherapy is one of commonly used adjuvant therapies in clinical patients with cerebral oedema such as osmotic dehydrating agents including mannitol and hypertonic saline (HS) that are widely used to relieve cerebral oedema [3]. The group of Schwab has been reported that 10 % HS effective in reducing the common cerebral oedema, and for cases that failed with mannitol treatment [5]
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