Bypassing Androgens: CNS-Targeted Estrogen Delivery Res-cues the Gonadectomized Male Rat Visual Cortex Neuropro-teome

ABSTRACT: Mass spectrometry-based proteomics has become instrumental for elucidating the molec-ular mechanisms of neurodegeneration, enabling the identification of disease-associated proteomic alterations and protein-level responses to therapeutic interventions. Building on our previous proteomic characterization of the orchiectomized (ORX) male Brown Norway rat retina as a model of androgen deprivation, we extend this investigation to the visual cortex (VC), a key node in the visual pathway. Here we report the first comprehen-sive proteomic characterization of ORX-VC employing nanoflow liquid chromatog-raphy-tandem mass spectrometry, complemented by bioinformatic pathway analyses and quantitative assessment of candidate protein markers of ORX-induced changes. We fur-ther investigate whether 17β-estradiol (E2) supplementation is sufficient to counteract an-drogen deprivation-induced cortical proteomic disruption and restore visual system ho-meostasis. Our discovery-driven proteomics approach identified over 500 differentially expressed proteins following ORX. Pathway analyses revealed widespread proteomic dysregulation, with oxidative stress emerging as a primary driver. Estrogen receptor pre-dominance over androgen receptor signaling was also identified, consistent with our pre-vious findings in the ORX retina. Quantitative assessment of a candidate protein panel demonstrated that CNS-selective E2 delivery via its DHED (10β,17β-dihydroxyestra-1,4-dien-3-one) prodrug, acting independently of circulating tes-tosterone, substantially restored expression of key dysregulated proteins. These findings support central E2 supplementation as a viable neuroprotective strategy for maintaining sex hormone-dependent homeostasis in the androgen-deprived male visual system, with implications for patients undergoing androgen deprivation therapy at risk for visual pathway neurodegeneration.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Visual Cortex

SUBMITTER: Laszlo Prokai  

LAB HEAD: Laszlo Prokai, Ph.D., D.Sc

PROVIDER: PXD080391 | Pride | 2026-09-14

REPOSITORIES: Pride