Jack Ao, Glyn Chidlow, John Wood, Robert Casson

Purpose: Unregulated calpain activation is a well- recognized component of cellular ischaemic injury. We investigated the safety of a novel calpain inhibi- tor and its efficacy in preserving retinal ganglion cell (RGC) survival and function in a rat model of retinal ischaemic-reperfusion injury.
Methods: Safety study: Eyes (n=28) received intra- vitreal injection the calpain antagonist, or vehicle. ERG and OCT measurements were examined before and 7 days afterwards. RGC loss was determined by immunohistochemistry of retinal wholemounts.
Neuroprotection study: Rats received 75 minutes of pressure-induced retinal ischaemia to one eye. Fol- lowing ischaemia, a single intravitreal injection of the calpain antagonist or vehicle (n = 12) was delivered. The fellow eye served as an untreated control (n = 24). ERG and OCT measurements were taken before and 7 days following ischaemia. Animals were humanely killed for immunohistochemical analysis of retinal wholemounts and optic nerves.
Results: Safety study: Neither the calpain antagonist, at any concentration, nor vehicle caused any significant and consistent tissue damage up to 7 days after injection.
Neuroprotection study:. Eyes treated with the cal- pain antagonist had significantly increased (P < 0.001) survival of RGC, optic nerve protection, pres- ervation of ERG amplitude and retinal thickness compared to vehicle controls. Conclusion: Selective inhibition of calpain signifi- cantly augments RGC survival and function in reti- nal ischaemia, presenting a novel treatment for ischaemic retinal disease.