{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:34:57Z","timestamp":1788406497789,"version":"build-2803163510"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              For several decades, it has been recognized that overactivation of the glutamate-gated N-methyl-D-aspartate receptors (NMDARs) and subsequent Ca\n              <jats:sup>2+<\/jats:sup>\n              toxicity play a critical role in ischemic brain injury. 24S-hydroxycholesterol (24S-HC) is a major cholesterol metabolite in the brain, which has been identified as a potent positive allosteric modulator of NMDAR in rat hippocampal neurons. We hypothesize that 24S-HC worsens ischemic brain injury via its potentiation of the NMDAR, and reducing the production of 24S-HC by targeting its synthetic enzyme CYP46A1 provides neuroprotection.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>We tested this hypothesis using electrophysiological, pharmacological, and transgenic approaches and in vitro and in vivo cerebral ischemia models.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Our data show that 24S-HC potentiates NMDAR activation in primary cultured mouse cortical neurons in a concentration-dependent manner. At 10 \u00b5mol\/L, it dramatically increases the steady-state currents by 51% and slightly increases the peak currents by 20%. Furthermore, 24S-HC increases NMDA and oxygen-glucose deprivation\u2013induced cortical neuronal injury. The increased neuronal injury is largely abolished by NMDAR channel blocker MK-801, suggesting an NMDAR-dependent mechanism. Pharmacological inhibition of CYP46A1 by voriconazole or gene knockout of\n              <jats:italic toggle=\"yes\">Cyp46a1<\/jats:italic>\n              dramatically reduces ischemic brain injury.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>These results identify a new mechanism and signaling cascade that critically impacts stroke outcome: CYP46A1 \u2192 24S-HC \u2192 NMDAR \u2192 ischemic brain injury. They offer proof of principle for further development of new strategies for stroke intervention by targeting CYP46A1 or its metabolite 24S-HC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.124.047803","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T09:02:01Z","timestamp":1725354121000},"page":"2492-2501","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Role of Cholesterol Metabolic Enzyme CYP46A1 and Its Metabolite 24S-Hydroxycholesterol in Ischemic Stroke"],"prefix":"10.1161","volume":"55","author":[{"given":"Huawei","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger P.","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2824-4168","authenticated-orcid":true,"given":"Zhi-gang","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2072-4340","authenticated-orcid":true,"given":"Tiandong","family":"Leng","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0b013e3182009701"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(08)60694-7"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.4103\/bc.bc_36_18"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706442"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000143219.16695.af"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000226651.04862.da"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6093256"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(95)80018-W"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2996146"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.str.0000025518.34157.51"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(02)00164-3"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.2174\/1566524043479248"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1159\/000074808"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2010.12.008"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.11.006"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.236273"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010715-103233"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.2000.80.1.361"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303415200"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.13.7238"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2619-13.2013"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12318"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0344-14.2014"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.08.026"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16660986"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3504"},{"key":"e_1_3_3_29_2","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/S0022-3565(25)11027-6","article-title":"N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture.","volume":"243","author":"Goldberg MP","year":"1987","unstructured":"Goldberg MP, Weiss JH, Pham PC, Choi DW. 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