We previously reported that elevated pressure induces axonal swelling and facilitates the synthesis of the
neurosteroid,
allopregnanolone (AlloP), in the ex vivo rat retina. Exogenously applied AlloP attenuates the axonal swelling, suggesting that the
neurosteroid plays a neuroprotective role against glaucomatous pressure-induced
injuries, although mechanisms underlying neurosteroidogenesis have not been clarified. The aim of this study was to determine whether AlloP synthesis involves activation of translocator
protein 18 kD (TSPO) and whether TSPO modulates pressure-induced
retinal injury. Ex vivo rat retinas were exposed to various pressures (10, 35, or 75 mmHg) for 24 h. Expression of TSPO, 5α-reductase (5aRD), and AlloP was examined by quantitative real-time RT-PCR, ELISA, immunohistochemistry, and LC-MS/MS. We also examined the effects of TSPO
ligands on AlloP synthesis and
retinal damage. In this acute model, quantitative real-time RT-PCR and ELISA analyses revealed that elevated pressure facilitated TSPO expression. Similarly, these methods also detected enhanced 5aRD (mostly type II), which was observed in retinal ganglion cells (RGC) and the inner nuclear layer (INL). Atriol, a TSPO antagonist, suppressed pressure mediated AlloP synthesis and induced more severe histological changes in the inner retina when combined with elevated pressure.
PK11195, a TSPO
ligand that facilitates AlloP synthesis by itself, remarkably diminished pressure-mediated
retinal degeneration. These results suggest that AlloP synthesis is induced by sequential activation of TSPO and 5aRD in an ex vivo
glaucoma model, and that TSPO agonists may serve as potential therapeutic agents for the prevention of pressure-induced
retinal damage.