Format

Send to

Choose Destination
Invest Ophthalmol Vis Sci. 2014 Sep 4;55(10):6350-7. doi: 10.1167/iovs.13-13708.

Caspase-9 mediates photoreceptor death after blunt ocular trauma.

Author information

1
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.
2
Neurotrauma Research Group, Neurobiology Section, Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom.
3
Department of Pathology and Cell Biology, Columbia University, New York, New York, United States.
4
University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom.
5
Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, United Kingdom Birmingham and Midland Eye Centre, Birmingham, United Kingdom.

Abstract

PURPOSE:

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.

KEYWORDS:

apoptosis; caspase-9; commotio retinae; photoreceptors; trauma

PMID:
25190658
PMCID:
PMC4580085
DOI:
10.1167/iovs.13-13708
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center