Bim inhibition ameliorates visual loss and promotes axon regeneration by upregulation of Drd1 expression.

This study evaluated the neuroprotective effects of inhibiting the pro-apoptotic molecule Bim (Bcl-2-interacting mediator of cell death) in retinal ganglion cells (RGCs). A mouse optic nerve crush (ONC) model was used to induce RGC degeneration. Bim expression and RGC survival were assessed by immunohistochemistry, RBPMS immunofluorescence, and histological analyses. Following intravitreal injection of AAV2-shBim, retinal structure and visual function were evaluated by optical coherence tomography, flash visual evoked potentials, and flash electroretinography. Optic nerve axons were assessed by CTB-555 anterograde tracing. Primary dorsal root ganglion (DRG) neurons were used to examine the effects of Bim manipulation on axon growth. RNA sequencing, qPCR, and pharmacological modulation of Drd1 signaling were performed to investigate associated molecular changes. ONC induced marked upregulation of Bim expression accompanied by substantial RGC loss. AAV2-shBim treatment reduced Bim expression, preserved retinal structure, increased RGC survival, partially improved visual function, and enhanced axonal preservation after injury. In DRG cultures, Bim knockdown promoted axon elongation, whereas Bim overexpression suppressed axon growth. Transcriptomic analysis identified significant upregulation of Drd1 following Bim inhibition, which was confirmed by qPCR. Pharmacological activation of DRD1 enhanced axon growth, whereas DRD1 blockade attenuated this effect. Taken together, these findings indicate that Bim inhibition is associated with enhanced RGC survival and axonal preservation after ONC, with Drd1 related signaling potentially contributing to these effects.