{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T04:39:33Z","timestamp":1774931973400,"version":"3.50.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T00:00:00Z","timestamp":1647388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH101874"],"award-info":[{"award-number":["MH101874"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>In an <jats:italic>ex vivo<\/jats:italic> rat ocular hypertension (OHT) model, the neurosteroid allopregnanolone (AlloP) exerts neuroprotective effects via enhancement of both GABA<jats:sub>A<\/jats:sub> receptors and autophagy. We now examine whether its enantiomer (<jats:italic>ent-<\/jats:italic>AlloP), which is largely inactive at GABA receptors, offers similar neuroprotection in <jats:italic>ex vivo<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> rat OHT models. <jats:italic>Ex vivo<\/jats:italic> rat retinal preparations were incubated in a hyperbaric condition (10 and 75\u00a0mmHg) for 24\u00a0h. An <jats:italic>in vivo<\/jats:italic> ocular hypertension (OHT) model was induced by intracameral injection of polystyrene microbeads. We examined pharmacological effects of AlloP, <jats:italic>ent-<\/jats:italic>AlloP, picrotoxin (a GABA<jats:sub>A<\/jats:sub> receptor antagonist), and 3-MA (an autophagy inhibitor) histologically and biochemically. We found that both AlloP and <jats:italic>ent<\/jats:italic>-AlloP have marked neuroprotective effects in the retina, but effects of the unnatural enantiomer are independent of GABA<jats:sub>A<\/jats:sub> 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). <jats:italic>ent<\/jats:italic>-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 <jats:italic>ent<\/jats:italic>-AlloP further enhanced LC3B-II and suppressed SQSTM1, indicating that autophagy is a major mechanism underlying neuroprotection by <jats:italic>ent<\/jats:italic>-AlloP. In an rat <jats:italic>in vivo<\/jats:italic> OHT model, single intravitreal <jats:italic>ent<\/jats:italic>-AlloP injection prevented apoptotic cell death of retinal ganglion cells similar to AlloP. However, even in this model, <jats:italic>ent<\/jats:italic>-AlloP was more effective in activating autophagy than AlloP. We conclude that <jats:italic>ent<\/jats:italic>-AlloP may be a prototype of potential therapeutic for treatment of glaucoma as an autophagy enhancer without affecting GABA receptors.<\/jats:p>","DOI":"10.3389\/fphar.2022.855779","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T07:40:23Z","timestamp":1647416423000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["The Enantiomer of Allopregnanolone Prevents Pressure-Mediated Retinal Degeneration Via Autophagy"],"prefix":"10.3389","volume":"13","author":[{"given":"Makoto","family":"Ishikawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Nakazawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Kunikata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kota","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Yoshitomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathiresan","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas F.","family":"Covey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles F.","family":"Zorumski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukitoshi","family":"Izumi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.bbamem.2006.07.011","article-title":"Lack of Enantiomeric Specificity in the Effects of Anesthetic Steroids on Lipid Bilayers","volume":"1768","author":"Alakoskela","year":"2007","journal-title":"Biochim. 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