Abstract
AbstractPurpose: To investigate the dose/response curve, therapeutic window, length of treatment and protective effects of ITH‐IB6 on retinal ganglion cell (RGC) survival in a model of NMDA‐induced excitotoxicity.Methods: Adult Sprague Dawley rats received in their left eye an intravitreal injection of 100 mM NMDA and were treated with subcutaneous (sc) injections of vehicle (1% DMSO in saline) or ITH‐IB6 diluted in vehicle. For the dose–response study different concentrations of ITH‐IB6 (1, 3, 10, 10, 30, or 60 mg/kg) were injected for 7 days (d). To determine the therapeutic window, ITH‐IB6 was administered 12 hours (h) before or 1, 12 or 24 h after NMDA injection. To investigate duration of treatment with optimal results, ITH‐IB6 was administered for 1, 2, 3 or 7d after NMDA. Using optimal treatment protocols obtained from the above mentioned studies, ITH‐IB6‐afforded protection was studied in vivo with OCT (before processing each animal) to examine retinal thickness, and ex vivo by quantifying surviving RGCs. Retinas were analysed 7, 14 or 21d after NDMA injection and sc ITH‐IB6.Results: The dose–response study showed significant protection with 10 or 30 mg/kg ITH‐IB6, best protection was obtained when treatment was initiated 12 h before NMDA injection and the length of treatment study documented that sc ITH‐IB6 administration for 3d provided optimal effects. In vivo, significant retinal thickness preservation was observed in ITH‐IB6‐treated when compared to vehicle‐treated rats. Ex vivo results showed that in contrast to saline, ITH‐IB6 afforded significant protection of Brn3a + RGCs at 7, 14 and 21d, respectively, after NDMA injection.Conclusions: sc ITH‐IB6 (30 mg/kg) administered 12 h before NMDA‐induced retinal injury for 3d, protects RGCs against excitotoxicity‐induced RGC death.
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