Over Expression of Sigma-1 Receptor Protects Against Retinal Ganglion Cell loss in an Optic Nerve Crush Model.
Ellis, Dorette PhD
Yorio, Thomas PhD
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Purpose: Recent studies in sigma-1 receptors (σ-1r)- deficient mice demonstrated increased losses of retinal ganglion cells (RGCs) in oxidative stress and optic nerve crush mice models (ONC) . This study determines the neuroprotective role of the σ-1r in σ-1r- deficient mice ONC model. Methods: ONC was performed in σ-1r k/o mice and wild type mice. Briefly, the left optic nerve (ON) were exposed intraorbitally through a small window made between the surrounding muscles. The ON was crushed approximately 1mm behind the globe with self-closing forceps for 4 seconds under visualization. The contralateral eye was used as controls for ONC. Two weeks prior to ONC, mice were intravitreally injected with AAV2-CAG-σ-1r-GFP vector (1.2 x 1010) and expression of σ-1r was assessed; AAV2 empty vector (1.2 x 1010) served as controls. Termination experiments include counting RGCs using RNA-binding protein with multiple splicing antibodies (RBPMS antibodies) in experimental animals to determine neuroprotective activities of the σ-1r. Results: RGC death was accelerated in σ-1r k/o ONC animals when compared with wild-type mice. σ-1r k/o ONC mice injected with AAV2-CAG-σ-1r-GFP vector demonstrated significant increases in RGCs numbers and activity when compared with σ-1r k/o ONC mice injected with empty vector or non-injected σ-1r k/o ONC animals. Conclusion: Our studies which involved the expression of σ-1r in a system devoid of σ-1rs, provided direct evidence of neuroprotection of RGCs due to the expression of σ-1rs. These findings support a protective role of σ-1r in RGCs when they are challenged by neurodegenerative insults. Financial Disclosure: Supported by a grant from DOD (W81XWH-10-2-0003)