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Neuroprotective Effect of Sulfhydryl Reduction in a Rat Optic Nerve Crush Model

From the Department of Ophthalmology and Visual Science, University of Wisconsin Medical School, Madison, Wisconsin.

PURPOSE. The signaling of retinal ganglion cell (RGC) death after axotomy is partly dependent on the generation of reactive oxygen species. Shifting the RGC redox state toward reduction is protective in a dissociated mixed retinal culture model of axotomy. The hypothesis for the current study was that tris(2-carboxyethyl)phosphine (TCEP), a sulfhydryl reductant, would protect RGCs in a rat optic nerve crush model of axotomy.

METHODS. RGCs of postnatal day 4 to 5 Long-Evans rats were retrogradely labeled with the fluorescent tracer DiI. At approximately 8 weeks of age, the left optic nerve of each rat was crushed with forceps and, immediately after, 4 µL of TCEP (or vehicle alone) was injected into the vitreous at the pars plana to a final concentration of 6 or 60 µM. The right eye served as the control. Eight or 14 days after the crush, the animals were killed, retinal wholemounts prepared, and DiI-labeled RGCs counted. Bandeiraea simplicifolia lectin (BSL-1) was used to identify microglia.

RESULTS. The mean number of surviving RGCs at 8 days in eyes treated with 60 µM TCEP was significantly greater than in the vehicle group (1250 ± 156 vs. 669 ± 109 cells/mm²; P = 0.0082). Similar results were recorded at 14 days. Labeling was not a result of microglia phagocytosing dying RGCs. No toxic effect on RGC survival was observed with TCEP injection alone.

CONCLUSIONS. The sulfhydryl-reducing agent TCEP is neuroprotective of RGCs in an optic nerve crush model. Sulfhydryl oxidative modification may be a final common pathway for the signaling of RGC death by reactive oxygen species after axotomy.