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Chloe Naomi Thomas, Tonia S Rex, Alexandra Bernardo-Colon, Richard J Blanch, Zubair Ahmed; Caspase-2 increases in RGC and its inhibition protects against optic nerve degeneration in a murine repeated blast ocular trauma model.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4450. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Caspase-2 is activated in retinal ganglion cells (RGC) in optic nerve crush (ONC) model and after blunt ocular trauma. Caspase-2 also promotes neuronal degeneration in Alzheimer’s disease. RGC are CNS neurons and do not regenerate after injury, thus after injury RGC and their axons (which form the optic nerve) are not replaced, which can lead to potentially irreversible blindness. Our aim was to determine if caspase-2 is activated in a murine repeated blast ocular trauma model and whether its inhibition using a siRNA to caspase-2 (siCASP2) prevents RGC and optic nerve degeneration.
We exposed the left eye of anesthetised C57Bl/6 mice to repeated blast of overpressure air (2 x 15psi blasts in quick succession, 24 hours apart over 3 days). Sham mice were exposed to anaesthetics but not the blast wave. Eyes were collected 1 month after blasts and immunostained for caspase-2 (n=4). The siCASP2 was intravitreally injected 2 days before injury and every 7 days during the experiment until collection. Eyes were sectioned and the RGC were immunolabelled, and optic nerves were resin embedded, sectioned, and stained with p-phenylenediamine (PPD) and toluidine blue (n=5 optic nerves per group). Total RGC and healthy and degenerating axons were counted. Optical coherence tomography (OCT) imaging of the retina was performed throughout the experiment. siCASP2 was generously donated by Quark Pharmaceuticals Inc, without interference with study design or its outcome.
Caspase-2 immunofluorescence increased in RGC in 1 month C57Bl/6 mouse exposed to repeated blast, compared to sham. There was a decrease in total degenerating axons in siCASP2 treated optic nerves compared to siGFP control (80 ± 18 compared to 166 ± 22; n=5; students t-test p<0.05). There was no difference in total axons (p>0.05). This suggests that siCASP2 prevents axonal degeneration after repeated blast injury. OCT imaging showed that intravitreal injections and repeated blast does not affect gross retinal structure.
Caspase-2 is increased in RGC after repeated blast ocular trauma and siCASP2 treatment protects against degeneration of axons in the optic nerve. These data suggest that this may be a common pathogenic pathway in both blunt and blast force induced neurotrauma.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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