Sigma 1 Receptor Modulates Optic Nerve Head Astrocyte Reactivity

PURPOSE: Stimulation of Sigma 1 Receptor (S1R) is neuroprotective in retina and optic nerve. S1R is expressed in both neurons and glia. The purpose of this work is to evaluate the ability of S1R to modulate reactivity responses of optic nerve head astrocytes (ONHAs) by investigating the extent to which S1R activation alters ONHA reactivity under conditions of ischemic cellular stress. METHODS: Wild type (WT) and S1R knockout (KO) ONHAs were derived and treated with vehicle or S1R agonist, (+)-pentazocine ((+)-PTZ). Cells were subjected to six hours of oxygen glucose deprivation (OGD) followed by 18 hours of re-oxygenation (OGD/R). Astrocyte reactivity responses were measured. Molecules that regulate ONHA reactivity, signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-kB), were evaluated. RESULTS: Baseline glial fibrillary acidic protein (GFAP) levels were increased in nonstressed KO ONHAs compared with WT cultures. Baseline cellular migration was also increased in nonstressed KO ONHAs compared with WT. Treatment with (+)-PTZ increased cellular migration in nonstressed WT ONHAs but not in KO ONHAs. Exposure of both WT and KO ONHAs to ischemia (OGD/R), increased GFAP levels and cellular proliferation. However, (+)-PTZ treatment of OGD/R-exposed ONHAs enhanced GFAP levels, cellular proliferation, and cellular migration in WT but not KO cultures. The (+)-PTZ treatment of WT ONHAs also enhanced the OGD/R-induced increase in cellular pSTAT3 levels. However, treatment of WT ONHAs with (+)-PTZ abrogated the OGD/R-induced rise in NF-kB(p65) activation. CONCLUSIONS: Under ischemic stress conditions, S1R activation enhanced ONHA reactivity characteristics. Future studies should address effects of these responses on RGC survival.