Activation of Sigma 1 Receptor Preserves Visual Function After Optic Nerve Injury.

PURPOSE: Previous research has indicated that sigma 1 receptor (Sig1R) activation can help retinal ganglion cells (RGCs) survive optic nerve injury. However, in these studies, the treatments were given before the injury. We explored whether activating Sig1R as a post-injury treatment can still preserve visual function. METHODS: Wild-type or Sig1R knockout mice were subjected to optic nerve crush (ONC) injury. The contralateral eye served as sham control. Starting 6 hours after ONC, (+)-pentazocine, or (+)-PTZ, was administered daily. Visual acuity, contrast sensitivity, pattern electroretinography (PERG), visual evoked potential (VEP), and imaging of retinal structure and vasculature were evaluated using OptoMotry, ERG, spectral-domain optical coherence tomography, and fluorescein angiography, respectively. Retinal neurons and RGC survival were assessed in retinal whole mounts, and retinal glial activation was detected through glial fibrillary acid protein (GFAP) immunolabeling on retinal cryosections. Oxidative stress levels were measured with dihydroethidium (DHE) staining. Additionally, quantitative reverse transcription PCR was conducted to analyze changes in mRNA expression related to antioxidant (Nrf2, HO-1, NQO1) and inflammatory (IL1β, TNFα, iNOS) pathways. RESULTS: Our results indicate that activating Sig1R with (+)-PTZ after ONC injury effectively preserves visual function. This was demonstrated by enhanced visual acuity, contrast sensitivity, PERG, and VEP responses, as well as improved retinal thickness and vasculature in ONC+PTZ mice. Additionally, activation of Sig1R limits ONC-induced neurodegeneration and glial activation caused by ONC by a mechanism involving increasing antioxidant genes expression (Nrf2, HO-1, NQO1) and decreasing retinal inflammation (IL1β, TNFα, iNOS). CONCLUSIONS: These findings suggest that activating Sig1R could be a promising therapeutic approach for preserving visual function even after optic nerve damage.