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Here we report that cholestane-3\u03b2,5\u03b1,6\u03b2-triol (triol), a major metabolite of cholesterol, is an endogenous neuroprotectant and protects against neuronal injury both<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>via negative modulation of NMDA receptors. Treatment of cultured neurons with triol protects against glutamate-induced neurotoxicity, and administration of triol significantly decreases neuronal injury after spinal cord ischemia in rabbits and transient focal cerebral ischemia in rats. An inducible elevation of triol is associated with ischemic preconditioning and subsequent neuroprotection in the spinal cord of rabbits. This neuroprotection is effectively abolished by preadministration of a specific inhibitor of triol synthesis. Physiological concentrations of triol attenuate [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>induced by glutamate and decrease inward NMDA-mediated currents in cultured cortical neurons and HEK-293 cells transiently transfected with NR1\/NR2B NMDA receptors. Saturable binding of [<jats:sup>3<\/jats:sup>H]triol to cerebellar granule neurons and displacement of [<jats:sup>3<\/jats:sup>H]MK-801 binding to NMDA receptors by triol suggest that direct blockade of NMDA receptors may underlie the neuroprotective properties. Our findings suggest that the naturally occurring oxysterol, the major cholesterol metabolite triol, functions as an endogenous neuroprotectant<jats:italic>in vivo<\/jats:italic>, which may provide novel insights into understanding and developing potential therapeutics for disorders in the CNS.<\/jats:p>","DOI":"10.1523\/jneurosci.0344-14.2014","type":"journal-article","created":{"date-parts":[[2014,9,8]],"date-time":"2014-09-08T22:26:19Z","timestamp":1410215179000},"page":"11426-11438","source":"Crossref","is-referenced-by-count":42,"title":["The Major Cholesterol Metabolite Cholestane-3\u03b2,5\u03b1,6\u03b2-Triol Functions as an Endogenous 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