title: Blocking endothelin-B receptors rescues retinal ganglion cells from optic nerve injury through suppression of neuroinflammation.
abstract: OBJECTIVE
  The endothelins (ETs) cause reactive astrogliosis, which involves neuroinflammation and neurodegeneration in the central nervous system. The purpose of this study was to determine whether blocking the ET signals will protect retinal ganglion cells (RGCs) from optic nerve injury.
  
  
  METHODS
  We studied the effect of pretreatment with BQ-123, an antagonist of ETA receptors, and BQ-788, an antagonist of ETB receptors, on the survival of RGCs after the optic nerve of rats was crushed. We also performed immunohistological evaluations and real-time PCR of the crushed site to determine the expressions of the ET-1, CD68, GFAP, TNF-α, and iNOS genes in the neuroinflammation of the optic nerves.
  
  
  RESULTS
  The mRNA levels of the ETB receptors were upregulated (5.6-fold) on day 7 after crushing the optic nerves. Cells expressing ETB receptors were recruited mainly to the crushed site where the immunoreactivity to GFAP was weak. These cells were also immuunoreactive to ETs and CD68, a constitutive marker of microglia/macrophages. In the adjacent areas, immunoreactivity to GFAP was intense. Crushing the optic nerve increased the mRNA levels of ET-1 (4.5-fold), CD68 (87.5-fold), GFAP (2-fold), TNF-α (480-fold), and iNOS (6-fold) on day 7. Pretreatment with BQ-788 significantly suppressed the upregulation of these genes and loss of RGCs on day 7, whereas BQ-123 failed to protect the RGCs.
  
  
  CONCLUSIONS
  These results suggest that the microglia/macrophages recruited to the crushed site are the possible cellular sources of the ETs, which caused reciprocal activation of astrocytes. Blocking the ETB receptors by BQ-788 rescued RGCs, most likely by attenuating neuroinflammatory events.
authors.affiliation: Department of Ophthalmology, Osaka Medical College, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tonari
authors.forename: Takuji
authors.initials: T
authors.lastname: Kurimoto
authors.forename: Taeko
authors.initials: T
authors.lastname: Horie
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Ikeda
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Oku
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D002470:Cell Survival / Q000502:physiology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D008297:Male; D017628:Microglia / Q000502:physiology; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology*; D020221:Optic Nerve Injuries / Q000235:genetics / Q000517:prevention & control*; D009902:Optic Neuritis / Q000235:genetics / Q000517:prevention & control*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D044022:Receptor, Endothelin A / Q000235:genetics; D044023:Receptor, Endothelin B / Q000235:genetics; D012165:Retinal Ganglion Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D005904:Glial Fibrillary Acidic Protein; D052247:Nitric Oxide Synthase Type II; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014409:Tumor Necrosis Factor-alpha; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C086539:BQ 788; C496318:Nos2 protein, rat; C072247:cyclo(Trp-Asp-Pro-Val-Leu)