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Retinal injury due to excessive light exposure during military duties often results in serious vision damage to soldiers including irreversible loss of visual function. However, therapeutic interventions that can promote retinal protection or reverse retinal damage are very limited. This unmet clinical need also persists in the public when strong lasers, light, or fire cause trauma in ocular tissues. It is well known that estrogen has been shown to exhibit various beneficial actions in the central nervous system, including positively affecting mood and protecting the neuronal cells against neurodegenerative diseases. Despite estrogen's potential, its detrimental side effects prevent its clinical uses for neurotherapy. To overcome this challenge, a bioprecursor prodrug was developed, called 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), that is selectively converted to E2 only in the neuronal cells, including retinal cells. To determine if treatment with DHED can sufficiently protect the photoreceptor cells from light-induced damage, male C57BL/6J mice were injected with or without 100 μg/kg DHED (n=15), 200 μg/kg DHED (n=15), 400 μg/kg DHED (n=15) and 200 μg/kg E2 (n=15) for 10 days before the light injury. Seven days after the light exposure, the visual function and retinal structure were examined by the spectral-domain optical coherence tomography (SD-OCT) and electroretinogram (ERG). After light exposure, we found massive photoreceptor loss as indicated by thinning of the outer nuclear layer (ONL) in groups that received no treatment. However, DHED treatment significantly prevented light-induced retinal structural changes and light-induced a- and b-wave reduction. Additionally, photoreceptor loss was decreased as indicated by increased outer nucellar layer thickness and SD-OCT data. The photoreceptor protective effects upon DHED-derived E2 treatment are stronger than that of the direct E2 treatment, consistent with our earlier observation that targeted E2 delivery via DHED prodrug produces more robust neuroprotection than direct administration of E2. In conclusion, our study supported our hypothesis that DHED is an efficacious and safe site-specific delivery agent to produce robust estrogen-mediated retinal neuroprotection.