{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:33:16Z","timestamp":1791275596206,"version":"4.1.0"},"reference-count":31,"publisher":"National Academy of Sciences","issue":"37","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,9,12]]},"abstract":"<jats:p>\n                    Niemann\u2013Pick type C1 (NPC1) disease is a fatal neurodegenerative disease characterized by neuronal lipid storage and progressive Purkinje cell loss in the cerebellum. We investigated whether therapeutic approaches to bypass the cholesterol trafficking defect in NPC1 disease might delay disease progression in the\n                    <jats:italic>npc1<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mouse model. We show that the neurosteroid allopregnanolone (ALLO) and T0901317, a synthetic oxysterol ligand, act in concert to delay onset of neurological symptoms and prolong the lifespan of\n                    <jats:italic>npc1<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. ALLO and T0901317 therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes and inflammatory mediators, and reduced infiltration of activated microglia in the cerebellar tissue. To establish whether the mechanism of neuroprotection in\n                    <jats:italic>npc1<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice involves GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor activation, we compared treatment of natural ALLO and\n                    <jats:italic>ent<\/jats:italic>\n                    -ALLO, a stereoisomer that has identical physical properties of natural ALLO but is not a GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor agonist.\n                    <jats:italic>ent<\/jats:italic>\n                    -ALLO provided identical functional and survival benefits as natural ALLO in\n                    <jats:italic>npc1<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, strongly supporting a GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor-independent mechanism for ALLO action. On the other hand, the efficacy of ALLO,\n                    <jats:italic>ent<\/jats:italic>\n                    -ALLO, and T0901317 therapy correlated with the ability of these compounds to activate pregnane X receptor-dependent pathways\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These findings suggest that treatment with pregnane X receptor ligands may be useful clinically in delaying the progressive neurodegeneration in human NPC disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0606218103","type":"journal-article","created":{"date-parts":[[2006,8,30]],"date-time":"2006-08-30T04:27:46Z","timestamp":1156912066000},"page":"13807-13812","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":156,"title":["Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann\u2013Pick C disease"],"prefix":"10.1073","volume":"103","author":[{"given":"S. Joshua","family":"Langmade","sequence":"first","affiliation":[{"name":"*Center for Cardiovascular Research, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Gale","sequence":"additional","affiliation":[{"name":"*Center for Cardiovascular Research, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrey","family":"Frolov","sequence":"additional","affiliation":[{"name":"*Center for Cardiovascular Research, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuko","family":"Mohri","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinuko","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Synthia H.","family":"Mellon","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA 94143; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven U.","family":"Walkley","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas F.","family":"Covey","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean E.","family":"Schaffer","sequence":"additional","affiliation":[{"name":"*Center for Cardiovascular Research, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S.","family":"Ory","sequence":"additional","affiliation":[{"name":"*Center for Cardiovascular Research, Department of Internal Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,9,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2004.08.011"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.35.21604"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003180200"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300488200"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)45483-X"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.23.8247"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304553200"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00227765"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5323.232"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.D300032-JLR200"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2004.08.017"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0010081"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302588200"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1073"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/383728a0"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105805200"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.16.6.0835"},{"key":"e_1_3_4_18_2","first-page":"1581","volume":"50","author":"Wittmer 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