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Editors Selection IGR 9-1
Basic research: Calpains
Comment by Cynthia Grosskreutz on:
17098 Calpain-specific proteolysis in primate retina: Contribution of calpains in cell death, Nakajima E; David LL; Bystrom C et al., Investigative Ophthalmology and Visual Science, 2006; 47: 5469-5475
Calpains are a family of calcium-activated cysteine proteases. Calpain activation has been implicated in neuronal death in a number of different injury conditions including ischemia, excitotoxicity, and acute ocular hypertension and calpain inhibition has been shown to be neuroprotective in a number of experimental paradigms. The purpose of the study by Nakajima et al. (93) was to investigate the involvement of calpain-induced proteolysis in retinal cell death in post-mortem human and monkey retinas. Retinal tissue culture was used to examine calpain activation either by oxygen and glucose deprivation or by the addition of exogenous calcium. Casein zymography and immunoblot analysis were used to demonstrate activation of calpain in hypoxic retina. The calpain inhibitor SJA6017 was seen to inhibit the appearance of substrate breakdown products as well as to inhibit the autolysis of full-length calpain. 2D-gel electrophoresis of monkey total retinal proteins was used to identify calcium-dependent differential protein expression. The involvement of calpain in the differential protein response was confirmed in 4 proteins by immunoblot. In sum, in this model, evidence for calpain-induced proteolysis was observed by the production of calpain specific spectrin breakdown products, production of calpain autolytic fragments, and cell death as indicated by LDH leakage under hypoxic conditions. These events were partially inhibited by the calpain inhibitor SJA6017, further supporting a role for calpain. Although the results of this study are provocative in their potential applicability to treatment of diseases such as glaucoma or ischemic retinopathy, a number of questions remain. First, large amounts of calcium were used in these studies and may not mimic in vivo conditions. In addition, the authors did not fully address the myriad of other events that are potentially mediated by increases in extracellular calcium or hypoxia and glucose deprivation. As acknowledged by the authors, additional work remains to determine specific cells or retinal layers most affected by activation of calpain. Although calpain inhibition has been shown to be neuroprotective under conditions of acute glaucoma, further study under more chronic conditions is the next step.
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