Bim Inhibition Ameliorates Visual Loss and Promotes Axon Regeneration by Up-Regulation of Drd1 Expression.

This study evaluated the neuroprotective effects of Bim (Bcl-2-interacting mediator of cell death) inhibition in retinal ganglion cells (RGCs) after optic nerve crush (ONC). Bim expression and RGC survival were assessed by immunohistochemistry, RNA-binding protein with multiple splicing (RBPMS) immunofluorescence, and histologic analyses. Following intravitreal injection of adeno-associated virus serotype 2-shRNA targeting Bim (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 cholera toxin subunit B-555 anterograde tracing. Primary dorsal root ganglion neurons were used to examine the effects of Bim manipulation on axon growth. RNA sequencing, quantitative RT-PCR, and pharmacologic dopamine receptor D1 (DRD1) modulation were performed to investigate downstream molecular changes. ONC markedly elevated Bim expression alongside substantial RGC loss. Adeno-associated virus serotype 2-shBim treatment reduced Bim expression, preserved retinal structure, increased RGC survival, partially improved visual function, and enhanced axonal preservation after injury. In dorsal root ganglion neuron cultures, Bim knockdown promoted axon elongation, whereas Bim overexpression suppressed axon growth. Transcriptomic analysis and quantitative PCR revealed up-regulation of Drd1 following Bim inhibition. Pharmacologic activation of DRD1 promoted axon growth, whereas DRD1 blockade attenuated this effect. Taken together, these findings indicate that Bim inhibition promotes RGC survival and axonal preservation after ONC, with Drd1-related signaling potentially contributing to these effects.