Amelioration of cold injury-induced cortical brain edema formation by selective endothelin ETB receptor antagonists in mice

PLoS One. 2014 Jul 7;9(7):e102009. doi: 10.1371/journal.pone.0102009. eCollection 2014.


Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice). Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV) administration of BQ788 (ETB antagonist), IRL-2500 (ETB antagonist), or FR139317 (ETA antagonist) prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / therapeutic use
  • Biphenyl Compounds / therapeutic use
  • Blood-Brain Barrier / drug effects
  • Blotting, Western
  • Brain Edema / etiology
  • Brain Edema / physiopathology
  • Brain Edema / prevention & control*
  • Brain Injuries / etiology
  • Brain Injuries / physiopathology
  • Brain Injuries / prevention & control*
  • Cerebrum / drug effects*
  • Cerebrum / injuries
  • Cerebrum / metabolism
  • Cold Temperature / adverse effects*
  • Dipeptides / therapeutic use
  • Endothelin Receptor Antagonists / therapeutic use*
  • Endothelins / genetics
  • Endothelins / metabolism
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Indoles / therapeutic use
  • Male
  • Mice
  • Oligopeptides / therapeutic use
  • Piperidines / therapeutic use
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Endothelin / chemistry*
  • Receptors, Endothelin / genetics
  • Receptors, Endothelin / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction


  • Azepines
  • Biphenyl Compounds
  • Dipeptides
  • Endothelin Receptor Antagonists
  • Endothelins
  • Glial Fibrillary Acidic Protein
  • IRL 2500
  • Indoles
  • Oligopeptides
  • Piperidines
  • RNA, Messenger
  • Receptors, Endothelin
  • FR 139317
  • BQ 788

Grant support

This work was supported by a Grant-in-Aid for Scientific Research (C) from the JPSP ( (grant No. 21590108). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.