Role of Sigma 1 Receptor in Retinal Degeneration of the Ins2(Akita/+) Murine Model of Diabetic Retinopathy

PURPOSE: Sigma receptor 1 (Sigma1R), a nonopioid putative molecular chaperone, has neuroprotective properties in retina. This study sought to determine whether delaying administration of (+)-pentazocine, a high-affinity Sigma1R ligand after onset of diabetes in Ins2(Akita/+) diabetic mice would afford retinal neuroprotection and to determine consequences on retinal phenotype in Ins2(Akita/+) diabetic mice in the absence of Sigma1R. METHODS: Ins2(Akita/+) diabetic and WT mice received intraperitoneal injections of (+)-pentazocine beginning 4 or 8 weeks after onset of diabetes; eyes were harvested at 25 weeks. Retinal histologic sections were analyzed to determine thicknesses of retinal layers, number of ganglion cells, and evidence of gliosis (increased glial fibrillary acidic protein levels). Ins2(Akita/+)/Sig1R(−/−)mice were generated and subjected to in vivo assessment of retinal architecture (optical coherence tomography [OCT]) and retinal vasculature using fluorescein angiography (FA) at 12 and 16 weeks compared with age-matched Ins2(Akita/+) mice. Eyes were then harvested for retinal morphometric assessment and gliosis assessment. RESULTS: Wild-type mice had 13 ± 0.06 cells/100 μm retinal length; cell bodies in Ins2(Akita/+) mice injected 4 and 8 weeks after onset of diabetes with (+)-pentazocine retained significantly more ganglion cells compared with Ins2(Akita/+) mice (9 ± 0.04) and demonstrated significant attenuation of gliosis. Ins2(Akita/+)/Sig1R(−/−)mouse retinas, analyzed to determine whether the Ins2(Akita/+) phenotype was accelerated when lacking Sigma1R, revealed increased nerve fiber layer thickness (OCT), evidence of vitreal opacities, and vessel beading (FA) compared with Ins2(Akita/+) mice. Morphometric analysis revealed significantly fewer ganglion cells in Ins2(Akita/+)/Sig1R(−/−)mice compared with Ins2(Akita/+) mice. CONCLUSIONS: Sigma1R may be a novel retinal stress modulator, and targeting it even after disease onset may afford retinal neuroprotection.