Purpose: Primary open angle glaucoma (POAG) is a leading cause of blindness, characterised by optic nerve head excavation and retinal ganglion cell degeneration. Recent studies have shown that inactivation of the serine protease inhibitor neuroserpin (SERPINI1) is associated with plasmin-proteolytic excitotoxicity within the retina, and the protective effects of SERPINI1 overexpression have been previously reported in various neurodegenerative diseases. Here, we examined the protective effects of exogenous intravitreal SERPINI1 administration on inner retinal function and structure in a mouse model of experimental glaucoma.
Methods: Wild-type C57BL/6J mice (n=32) were subject to weekly intracameral microbead injections for eight weeks, to induce a chronic increase in intraocular pressure (glaucoma, n=8). Human recombinant SERPINI1 was injected intravitreally in healthy (SERPINI1, n=8) and experimental glaucoma mice (glaucoma+SERPINI1, n=8; weekly). PBS was administered as a vehicle control (PBS, n=8). Functional changes were assessed using positive scotopic threshold response (pSTR) amplitude measurements. Retinal structural changes were investigated using hematoxylin and eosin staining of tissue sections and quantified by light microscopy.
Results: Exogenous SERPINI1 administration in experimental glaucoma mice demonstrated significant preservation of pSTR amplitudes when compared to glaucoma mice alone (p<0.02). Healthy control mice treated with the SERPINI1 protein showed no significant changes in pSTR amplitudes, when compared to untreated and PBS treated mice (p=0.19). Histological quantification further revealed no significant changes to GCL density in untreated, PBS and SERPINI1 alone treated groups (p=0.37). However, there was significant rescue of the GCL population in glaucoma mice that were administered SERPINI1 protein intravitreally, when compared to the glaucoma control mice (p<0.01).
Conclusions: This study establishes a protective effect of exogenous SERPINI1 administration on the retina in chronic glaucoma conditions. The molecule may impart protection by suppressing the excitotoxicity associated with plasmin proteolytic actions. The exact molecular mechanisms of SERPINI1 effects and consequences of its loss however remain undefined. Future proteomics investigations will establish the SERPINI1 signalling networks that are involved in retinal neuroprotection in glaucoma.