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

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/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.