title: The major cholesterol metabolite cholestane-3β,5α,6β-triol functions as an endogenous neuroprotectant.
abstract: Overstimulation of NMDA-type glutamate receptors is believed to be responsible for neuronal death of the CNS in various disorders, including cerebral and spinal cord ischemia. However, the intrinsic and physiological mechanisms of modulation of these receptors are essentially unknown. Here we report that cholestane-3β,5α,6β-triol (triol), a major metabolite of cholesterol, is an endogenous neuroprotectant and protects against neuronal injury both in vitro and in vivo 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(2+)]i 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 [(3)H]triol to cerebellar granule neurons and displacement of [(3)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 in vivo, which may provide novel insights into understanding and developing potential therapeutics for disorders in the CNS.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Departments of Pharmacology and.
authors.forename: Yuehan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Departments of Pharmacology and.
authors.forename: Tiandong
authors.initials: T
authors.lastname: Leng
authors.affiliation: Departments of Pharmacology and.
authors.forename: Ailing
authors.initials: A
authors.lastname: Liu
authors.affiliation: Departments of Pharmacology and.
authors.forename: Youqiong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: You
authors.affiliation: Departments of Pharmacology and.
authors.forename: Jingkao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Departments of Pharmacology and.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Tang
authors.affiliation: Departments of Pharmacology and.
authors.forename: Wenli
authors.initials: W
authors.lastname: Chen
authors.affiliation: Departments of Pharmacology and.
authors.forename: Pengxin
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Biochemistry, Zhongshan School of Medicine and.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: Departments of Pharmacology and.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Departments of Pharmacology and.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Physiology, School of Medicine, Ji-nan University, Guangzhou, Guangdong 510632, China, and.
authors.forename: Liwei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Pharmacology and Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China ygm@mail.sysu.edu.cn hfsang@fmmu.edu.cn.
authors.forename: Hanfei
authors.initials: H
authors.lastname: Sang
authors.affiliation: Departments of Pharmacology and ygm@mail.sysu.edu.cn hfsang@fmmu.edu.cn.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
mesh_terms: D000328:Adult; D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology; D002777:Cholestanols / Q000097:blood / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020760:Spinal Cord Ischemia / Q000517:prevention & control*; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: D002777:Cholestanols; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; C000474:cholestane-3,5,6-triol; D018698:Glutamic Acid; D016291:Dizocilpine Maleate
keywords: NMDA; calcium; cerebral ischemia; cholestane-3β, 5α, 6β-triol; spinal cord ischemia; steroid