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Abstract #99345 Published in IGR 22-4
The Enantiomer of Allopregnanolone Prevents Pressure-Mediated Retinal Degeneration Via Autophagy
Ishikawa M; Nakazawa T; Kunikata H; Sato K; Yoshitomi T; Krishnan K; Covey DF; Zorumski CF; Izumi YFrontiers in pharmacology 2022; 13: 855779
In an rat ocular hypertension (OHT) model, the neurosteroid allopregnanolone (AlloP) exerts neuroprotective effects via enhancement of both GABA receptors and autophagy. We now examine whether its enantiomer (AlloP), which is largely inactive at GABA receptors, offers similar neuroprotection in and rat OHT models. rat retinal preparations were incubated in a hyperbaric condition (10 and 75 mmHg) for 24 h. An ocular hypertension (OHT) model was induced by intracameral injection of polystyrene microbeads. We examined pharmacological effects of AlloP, AlloP, picrotoxin (a GABA receptor antagonist), and 3-MA (an autophagy inhibitor) histologically and biochemically. We found that both AlloP and -AlloP have marked neuroprotective effects in the retina, but effects of the unnatural enantiomer are independent of GABA receptors. Electron microscopic analyses show that pressure elevation significantly increased autophagosomes (APs) in the nerve fiber layer and addition of AlloP also increased APs and degenerative autophagic vacuoles (AVds). -AlloP markedly increased APs and AVds compared to AlloP. Examination of LC3B-II and SQSTM1 protein levels using immunoblotting revealed that AlloP increased LC3B-II, and -AlloP further enhanced LC3B-II and suppressed SQSTM1, indicating that autophagy is a major mechanism underlying neuroprotection by -AlloP. In an rat OHT model, single intravitreal -AlloP injection prevented apoptotic cell death of retinal ganglion cells similar to AlloP. However, even in this model, -AlloP was more effective in activating autophagy than AlloP. We conclude that -AlloP may be a prototype of potential therapeutic for treatment of glaucoma as an autophagy enhancer without affecting GABA receptors.
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