title: Caspase-9 mediates photoreceptor death after blunt ocular trauma.
abstract: OBJECTIVE
  Ocular trauma is common in civilian and military populations. Commotio retinae involves acute disruption of photoreceptor outer segments after blunt ocular trauma, with subsequent photoreceptor apoptosis causing permanent visual impairment. The mechanisms of photoreceptor death in commotio retinae have not previously been described, although caspase-dependent death is important in other nontraumatic retinal degenerations. We assessed the role of caspase-9 as a mediator of photoreceptor death in a rat model of ballistic ocular trauma causing commotio retinae.
  
  
  METHODS
  Bilateral commotio retinae was induced in rats by ballistic ocular trauma. Caspase-9 activity was assessed by immunohistochemistry, Western blotting, and bVAD-fmk active caspase capture. Caspase-9 was inhibited by unilateral intravitreal injection of highly specific X-linked inhibitor of apoptosis (IAP) baculoviral IAP repeat 3 (XBIR3) domain linked to the cell transduction peptide penetratin 1 (Pen-1) after ballistic injury, and the affected eyes were compared with control eyes treated with Pen-1 injection alone, and retinal function was assessed by electroretinogram a-wave amplitude and photoreceptor survival by outer nuclear layer thickness.
  
  
  RESULTS
  Increased levels of cleaved caspase-9 were shown in photoreceptors 5 hours after injury, and catalytically active full-length caspase-9 was isolated from retinas. Photoreceptor death after commotio retinae was reduced by caspase-9 inhibition by using Pen-1-XBIR3, and electroretinographic measurements of photoreceptor function was preserved, providing structural and functional neuroprotection.
  
  
  CONCLUSIONS
  The time course of caspase-9 activation and the neuroprotective effects of inhibition suggest that caspase-9 initiates cell death in a proportion of photoreceptors after blunt ocular trauma and that an intravitreally delivered biologic inhibitor may be an effective translational treatment strategy.
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, United Kingdom.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Blanch
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Zubair
authors.initials: Z
authors.lastname: Ahmed
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Thompson
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York, United States.
authors.forename: Nsikan
authors.initials: N
authors.lastname: Akpan
authors.affiliation: University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom.
authors.forename: David R J
authors.initials: DR
authors.lastname: Snead
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Berry
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York, United States.
authors.forename: Carol M
authors.initials: CM
authors.lastname: Troy
authors.affiliation: Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, United Kingdom Birmingham and Midland Eye Centre, Birmingham, United Kingdom.
authors.forename: Robert A H
authors.initials: RA
authors.lastname: Scott
authors.affiliation: Neurotrauma Research Group, Neurobiology Section, Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Ann
authors.initials: A
authors.lastname: Logan
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053453:Caspase 9 / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D004596:Electroretinography; D004789:Enzyme Activation; D005131:Eye Injuries / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020419:Photoreceptor Cells, Vertebrate / Q000201:enzymology / Q000473:pathology*; D051381:Rats; D041623:Tomography, Optical Coherence; D014949:Wounds, Nonpenetrating / Q000201:enzymology / Q000473:pathology*
chemical_list: D053453:Caspase 9
keywords: apoptosis; caspase-9; commotio retinae; photoreceptors; trauma