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Gulgun Tezel, Xiangjun Yang; Caspase-8 inhibition for immunomodulation and neuroprotection in glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2436.
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Caspase-8 is activated in the glaucomatous retina, and its inhibition provides some protection against RGC apoptosis in experimental models. However, caspase-8 also has pro-survival activity (in complex with cFLIPL) that suppresses RIPK-dependent necroptosis and promotes NF-κB-mediated inflammation through TNFR and TLR signaling. This study aimed to determine caspase-8-inhibiting treatment responses on opposing functions of caspase-8 in mouse glaucoma.
IOP elevation was induced by microbead/viscoelastic injections in mice. We injected a cell-permeable selective inhibitor of caspase-8 (zIETD-fmk, 50 µM) into the vitreous cavity of ocular hypertensive mice by 5 serial injections. An equal volume of vehicle (0.2% DMSO in PBS) was similarly injected in the control group of ocular hypertensive mice (n:5 in each group). Outcomes were compared between mice matched for the cumulative IOP exposure.
Similar to our previous studies, cleaved caspase-8 was detectable in RGCs but not in astrocytes isolated from ocular hypertensive retinas with over 30% axon loss. In contrast, astrocytes exhibited over two-fold increased expression of cFLIPL, while no prominent alteration in cFLIPL expression was visible in RGCs. Despite the lack of cleaved caspase-8, there was a six-fold increase in the catalytic caspase-8 activity in ocular hypertensive astrocytes. Retinal caspase-8 activity decreased nine-fold in zIETD-fmk-treated ocular hypertensive mice, verifying the drug delivery and biological function. Retinal caspase-8 inhibition resulted in cell-selective treatment responses. Compared to vehicle-treated controls, zIETD-fmk-treated retinas exhibited ~40% decrease in GFAP+ or Iba1+ cell counts (n:2 mice per group). When we compared axon counts between the zIETD-fmk-treated versus vehicle-treated ocular hypertensive mice (n:5 mice per group), we detected over 50% protection against axon loss at week 4 (14% with caspase-8 inhibitor versus 29% with vehicle).
Findings of this pilot study suggest that in addition to targeting RGC apoptosis, caspase-8 inhibition can also protect RGCs through an alternative mechanism by inducing the death of activated/inflammatory glia and preventing glia-mediated neuroinflammatory/neurodegenerative processes. Ongoing studies using transgenic models will better determine the potential of caspase-8 inhibition to protect RGCs from neurodegenerative inflammation by targeting the glia.
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