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Furthermore, 24SH (0.1\u2009\u00b5M) alone elevates AlloP levels via NMDA receptors. With this model, we now investigate possible interactions between 24SH and AlloP. We found that inhibition of AlloP synthesis with dutasteride under high pressure results in severe excitotoxicity in addition to axonal swelling. The excitotoxicity is prevented by exogenous AlloP but not 24SH, indicating that endogenous AlloP is crucial for protection. However, inhibition of 24SH synthesis with voriconazole induces severe excitotoxicity under normal pressure. Paradoxically, the excitotoxicity by voriconazole is better prevented by AlloP than 24SH. These findings suggest that inhibition of 24SH synthesis becomes excitotoxic in the absence of AlloP. We also observed that co-administration of sub-micromolar 24SH (0.1\u2009\u00b5M) and AlloP (0.1\u2009\u00b5M), concentrations that are only partially effective when administered alone, prevents axonal swelling under high pressure. This apparent enhanced protection indicates strong interaction between the two neurosteroids to preserve neuronal integrity, with 24SH contributing to AlloP synthesis via NMDA receptors and with AlloP playing an essential role in neuroprotection via GABA<jats:sub>A<\/jats:sub> receptors.<\/jats:p>","DOI":"10.1038\/s41598-018-31239-2","type":"journal-article","created":{"date-parts":[[2018,8,21]],"date-time":"2018-08-21T11:04:28Z","timestamp":1534849468000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Additive neuroprotective effects of 24(S)-hydroxycholesterol and allopregnanolone in an ex vivo rat glaucoma model"],"prefix":"10.1038","volume":"8","author":[{"given":"Makoto","family":"Ishikawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Yoshitomi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas F.","family":"Covey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles F.","family":"Zorumski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukitoshi","family":"Izumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,8,27]]},"reference":[{"key":"31239_CR1","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1136\/bjo.2005.081224","volume":"90","author":"HA Quigley","year":"2006","unstructured":"Quigley, H. 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C.F.Z. and D.F.C. own stock in Sage Therapeutics. M.I. and T.Y. receive lecture fees from Santen, Pfizer, Kowa, Otsuka, and Alcon. Y.I. has no financial conflicts of interest. DFC has an unpaid and non-financially supported collaboration involving research on cataracts with Viewpoint Therapeutics. Other authors declare no non-financial competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"12851"}}