September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Caspase-2 mediates retinal ganglion cell apoptosis in traumatic optic neuropathy caused by blunt ocular trauma.
Author Affiliations & Notes
  • Chloe Naomi Thomas
    Neurobiology, University of Birmingham, Birmingham, United Kingdom
  • Ann Logan
    Neurobiology, University of Birmingham, Birmingham, United Kingdom
  • Zubair Ahmed
    Neurobiology, University of Birmingham, Birmingham, United Kingdom
  • Richard J Blanch
    Neurobiology, University of Birmingham, Birmingham, United Kingdom
    Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, United Kingdom
  • Footnotes
    Commercial Relationships   Chloe Thomas, None; Ann Logan, None; Zubair Ahmed, None; Richard Blanch, None
  • Footnotes
    Support  Fight for Sight PhD Studentship (Grant code: 1560/1561)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 744. doi:
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      Chloe Naomi Thomas, Ann Logan, Zubair Ahmed, Richard J Blanch; Caspase-2 mediates retinal ganglion cell apoptosis in traumatic optic neuropathy caused by blunt ocular trauma.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):744.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Traumatic optic neuropathy (TON) is a major cause of visual loss after brain and eye injury. TON can be direct – where the optic nerve is crushed or cut – or more commonly indirect – where brain or ocular injury is associated with secondary retinal ganglion cell (RGC) degeneration. After blunt ocular trauma, RGC degeneration occurs at and around the injury site, contributing to visual loss.

The cell death protease caspase-2 has features of both initiator and executioner caspases and its inhibition is RGC-neuroprotective in a number of animal models of RGC death. We hypothesised that caspase-2 mediates RGC apoptosis after blunt ocular trauma and its inhibition would reduce RGC death.

Methods : Anaesthetised adult rats were subjected to blunt ocular trauma and caspase-2 activity assessed by immunohistochemistry and western blotting. After blunt ocular trauma, caspase-2 expression was inhibited by unilateral intravitreal injection of chemically modified small interfering RNA molecule (siCASP2) with contralateral injection of siGFP as control. RGC survival was assessed by Brn3a positive cell counts on sagittal retinal sections. n=4-8 rats /analysis

Results : Cleaved caspase-2 immunolocalised to RGC at 5 and 48 hours in injured but not intact retina (Fig 1). Retinal levels of full length caspase-2 (30kDa) increased up to 24 hours after injury (p=0.002) and a cleaved fragment (12kDa) was elevated at 48 hours (Fig 2; p=0.035). Caspase-2 inhibition by intravitreal siCASP2 injection increased RGC survival peripheral but not central to the injury site (p<0.001; Generalised Estimating Equations).

Conclusions : Caspase-2 is active in RGCs after blunt ocular trauma and may contribute to RGC degeneration by apoptosis. Caspase-2 inhibition protects apoptotic RGC peripheral but not central to the injury site, as central cells are more likely to be necrotic. siCASP2 has the potential to be used therapeutically as a neuroprotective treatment in TON caused by blunt ocular trauma.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Figure 1. Cleaved Caspase-2 co-localised with Brn3a, confirming RGC localisation. Cleaved Caspase-2 is present 5 and 48 hours after injury, but not in intact retinae.

Figure 1. Cleaved Caspase-2 co-localised with Brn3a, confirming RGC localisation. Cleaved Caspase-2 is present 5 and 48 hours after injury, but not in intact retinae.

 

Figure 2. On western blots, full length retinal Caspase-2 (30kDa) increased up to 24 hours after injury (*p>0.005, ANOVA). Cleaved Caspase-2 fragment (12kDa) was elevated at 48 hours (**p=0.035, ANOVA).

Figure 2. On western blots, full length retinal Caspase-2 (30kDa) increased up to 24 hours after injury (*p>0.005, ANOVA). Cleaved Caspase-2 fragment (12kDa) was elevated at 48 hours (**p=0.035, ANOVA).

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