title: Naturally occurring marine steroid 24-methylenecholestane-3β,5α,6β,19-tetraol functions as a novel neuroprotectant.
abstract: Steroids have been shown to have multiple effects on the nervous system including neuroprotective activities, and they have the potential to be used for the treatment of neurodegenerative diseases. In this current study, we tested the hypothesis that the marine steroid 24-methylenecholestane-3β,5α,6β,19-tetraol (Tetrol) has a neuroprotective effect. (1) We synthesized Tetrol through a multiple step reaction starting from hyodeoxycholic acid (HDCA). (2) We then evaluated the neuroprotective effect of Tetrol with a glutamate-induced neuronal injury model in vitro. Tetrol concentration dependently increased the survival rate of cerebellar granule neurons challenged with toxic concentration of glutamate. Consistently, Tetrol significantly decreased glutamate-induced lactate dehydrogenase (LDH) release with a threshold concentration of 2.5 μM. (3) We further evaluated the neuroprotective effect of Tetrol in a middle cerebral artery occlusion (MCAO)-induced cerebral ischemia model in rat. Tetrol, at a dose of 12 mg/kg, significantly decreased MCAO-induced infarction volume by ∼50%. (4) Finally, we probed the mechanism and found that Tetrol concentration dependently attenuated N-methyl-d-aspartate (NMDA)-induced intracellular calcium ([Ca(2+)]i) increase with an IC50 of 7.8±0.62 μM, and inhibited NMDA currents in cortical neurons with an IC50 of 10.28±0.71 μM. Taken together, we have synthesized and characterized Tetrol as a novel neuroprotectant through negative modulation of NMDA receptors.
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China; Neuroscience Institute, Morehouse School of Medicine, 720 Westview Dr SW, Atlanta, GA 30329, USA.
authors.forename: Tiandong
authors.initials: T
authors.lastname: Leng
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China.
authors.forename: Ailing
authors.initials: A
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China.
authors.forename: Youqiong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, GD 510006, China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, GD 510006, China.
authors.forename: Shujia
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China.
authors.forename: Yuehan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China.
authors.forename: Xingwen
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China.
authors.forename: Pengxin
authors.initials: P
authors.lastname: Qiu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, GD 510006, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Hu
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, 720 Westview Dr SW, Atlanta, GA 30329, USA.
authors.forename: Zhi-gang
authors.initials: ZG
authors.lastname: Xiong
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, GD 510006, China. Electronic address: jingxiaz@163.com.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, Sun Yat-Sen University, 74 Zhongshan Road II, Guangzhou, GD 510080, China. Electronic address: ygm@mail.sysu.edu.cn.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
mesh_terms: D000818:Animals; D059001:Aquatic Organisms / Q000737:chemistry*; D002545:Brain Ischemia / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology; D002777:Cholestanols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018698:Glutamic Acid / Q000633:toxicity; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley
chemical_list: C000611375:24-methylenecholestane-3,5,6,19-tetraol; D002777:Cholestanols; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D016202:N-Methylaspartate
keywords: Cerebral ischemia; Glutamate toxicity; Marine steroid; NMDA; Neuroprotection