Cutamesine (SA4503) Protects Retinal Ganglion Cells in an Ocular Hypertension Model of Glaucoma Determined Using Detection of Apoptosing Retinal Cells Technology and RBPMS Cell Marker.

PURPOSE: This study aimed to evaluate the neuroprotective effects of cutamesine (SA4503), a potent sigma-1-receptor agonist (S1R-agonist), in rat models of retinal degeneration induced by elevated intraocular pressure (IOP) using the Detection of Apoptosing Retinal Cells (DARC) technology. A secondary aim was to test its effect in a rat retinal oxidative stress model.

METHODS

Ocular hypertension (OHT) model was induced in Dark Agouti rats via episcleral vein injection of hypertonic saline, while a retinal oxidative stress was induced in Sprague-Dawley rats by intravitreal rotenone injection. In the OHT model, cutamesine (10 nmol) and recombinant human nerve growth factor [rh-NGF (positive control); 0.09 nmol] were intravitreally administered. Their effects were evaluated using DARC technology and RNA-binding protein with multiple splicing (RBPMS) immunohistochemistry. In the oxidative stress model, cutamesine (10 and 300 nmol) was coadministered with rotenone, and neurofilament light chain (Nfl) gene expression was measured by RT-PCR.

RESULTS

OHT induced a significant elevation of IOP over 3 weeks, peaked at day 1 (P < 0.001), and gradually decreased by day 21. Cutamesine significantly reduced the number of DARC spots (P < 0.05) and preserved retinal ganglion cells labeled with RBPMS (P < 0.01), similar to rh-NGF (P < 0.01). In the oxidative stress model, cutamesine preserved retinal Nfl expression levels in a dose-dependent manner.

CONCLUSIONS

Cutamesine demonstrated significant neuroprotective activity in rat models of OHT and oxidative stress using DARC and RBPMS labeling techniques. These findings provide further evidence that S1R-agonists possess substantial neuroprotective potential and may be beneficial for patients with OHT/glaucoma.