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Editors Selection IGR 10-3

Basic Research - RGC: Caspase inhibitors protect RGC

Comment by Larry Wheeler on:

46353 Caspase inhibitors protect against NMDA-mediated retinal ganglion cell death, Schuettauf F; Stein T; Choragiewicz TJ et al., Clinical and Experimental Ophthalmology, 2011; 39: 545-254

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Retinal ganglion cells(RGCs) express N-methyl-d-aspartate receptors (NMDA receptors) and are subject to cell death by over activation of these receptors by NMDA. As such NMDA receptors are highly regulated by membrane potential, requirements for agonists and co-agonists to function. The aim of the Schuettauf et al. (1516) paper was to identify specific downstream molecules that play a role in NMDA induced excitotoxicity as possible sites for neuroprotective drugs. NMDA induced RGC death is a common laboratory model in the rat to look for neuroprotective drugs. The authors focused on caspases as downstream targets in NMDA induced RGC death. There are at least 14 members of the caspase family. Caspases are cysteine proteases that can be divided into two basic classes: extrinsic (receptor mediated) and intrinsic (stress induced). Peptides that were specific inhibitors of the different caspases were injected intravitreally before NMDA. Results show that excitotoxic RGC death after NMDA was suggested to be mainly by apoptosis based on tunnel staining. Both intrinsic and extrinsic Caspases(1,3,4,6,8 and 9) were neuroprotective although not as protective as a channel blocker such as MK-801. This paper demonstrates the complexity of looking for new neuroprotective targets. The results show you can't use a specific downstream caspase inhibitor. In addition, caspases only partially protected RGCs from apoptosis no matter which one was used. In the discussion the Authors point out that recent research suggests that inhibition of caspases may promote alternative cell death pathways.

The paper concludes that caspases may be a promising downstream intervention that may not have the side effects associated with NMDA channel blockers. However, there are many challenges. These include the difficulty of delivery of small peptide antagonists or small molecule inhibitors to the back of the eye. And also the long term safety of blocking many caspases in the retina. What is their normal function? Do caspases alter visual processing, etc. The goal of safe neuroprotective compounds for the eye is an important goal. This paper is a reminder of complexity of the task ahead.

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