Transient ocular hypertension drives delayed and IOP-independent retinal neurodegeneration.

Glaucoma is a leading global cause of irreversible blindness, traditionally managed by controlling intraocular pressure (IOP). However, some patients continue to exhibit progressive visual decline despite successful IOP reduction, and the underlying pathological mechanisms remain elusive. To investigate this, we utilized a reversible ocular hypertension (OHT) rat model via anterior chamber silicone oil (SO) injection and subsequent aspiration. After one month of induced hypertension, IOP was fully normalized following SO aspiration. Visual function was longitudinally monitored for up to 6 months post-normalization using electrophysiological and behavioral assays. Corresponding pathological changes were assessed via immunofluorescence, H&E staining, transmission electron microscopy, and anterograde tracing. Additionally, Thy1-GFP transgenic mice were used to visualize the integrity of retinal ganglion cells (RGCs). Our findings reveal a biphasic progression of glaucomatous damage, transitioning from an early IOP-dependent phase to a late IOP-independent phase. Although IOP normalization partially rescues early visual function, a delayed deterioration emerges in the later stages. This late-stage decline is accompanied by persistent, non-IOP-dependent secondary factors following the relief of primary mechanical stress, including progressive RGCs loss, impaired axonal transport, persistent glial scarring, synaptic pruning, and dendritic atrophy. These results indicate that transient early IOP elevation induces long-term, delayed neurodegenerative changes, which ultimately compromise sustained functional recovery. Collectively, this study provides novel experimental evidence and identifies potential therapeutic targets, offering new insights into addressing glaucoma as a chronic, IOP-independent neurodegenerative disease and a universal clinical challenge.