Angiopoietin-Like 4 Attenuates Brain Edema and Neurological Deficits in a Mouse Model of Experimental Intracerebral Hemorrhage

Feb 13, 2018Medical science monitor : international medical journal of experimental and clinical research

Angiopoietin-Like 4 Reduces Brain Swelling and Improves Function After Brain Bleeding in Mice

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Abstract

Administration of recombinant human ANGPTL4 (40 µg/kg) reduced brain edema and hematoma volume in a mouse model of intracerebral hemorrhage.

RhANGPTL4 improved neurological functional recovery over a period of 4 weeks compared to the control group.
Treatment with ANGPTL4 significantly increased areas positive for VE-cadherin and claudin-5 in the peri-hematoma region.
A notable reduction in the ratio of phospho-Src to Src was observed in ANGPTL4-treated mice.
Decreased Src kinase activity in the peri-hematoma area was associated with lower vascular permeability and reduced edema formation.

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BACKGROUND Angiopoietin-like 4 (ANGPTL4) is neuroprotective when administered acutely for the treatment of cerebral ischemia. The aim of the present study was to evaluate the preventive effects of ANGPTL4 on the formation of brain edema and to determine whether it promotes the recovery of neurological function following intracerebral hemorrhage (ICH). MATERIAL AND METHODS Recombinant human ANGPTL4 (rhANGPTL4; 40 µg/kg) or a vehicle was administered intraperitoneally 5 min prior to bacterial collagenase-induced ICH in male C57/B6J mice. Behavioral tests were performed prior to ICH and at days 1, 3, 7, 14, 21, and 28 after ICH. Brain edema and hematoma volume were examined separately using the wet weight/dry weight method and hematoxylin-eosin staining. The integrity of the tight and adherens junctions was quantified via immunofluorescence. The ultrastructure of the blood-brain barrier (BBB) was examined using transmission electron microscopy. Vascular endothelial (VE)-cadherin, claudin-5, Src, and phospho-Src in the ipsilateral and contralateral striatum were detected by Western blot analysis. RESULTS RhANGPTL4 reduced brain edema and hematoma volume and improved neurological functional recovery over the subsequent 4 weeks when compared with the control group. rhANGPTL4 significantly increased VE-cadherin and claudin-5-positive areas and relative amounts in the peri‑hematoma region compared with the control group. In addition, ANGPTL4 significantly reduced the ratio of phospho-Src to Src. The significant reduction of Src kinase activity in the peri‑hematoma region of ANGPTL-treated mice was paralleled by a decrease in vascular permeability and edema formation. CONCLUSIONS These results suggest that ANGPTL4 is a relevant target for vasculoprotection and cerebral protection during stroke.

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Angiopoietin-Like 4 Attenuates Brain Edema and Neurological Deficits in a Mouse Model of Experimental Intracerebral Hemorrhage

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