title: Ginsenoside Reduces Cognitive Impairment During Chronic Cerebral Hypoperfusion Through Brain-Derived Neurotrophic Factor Regulated by Epigenetic Modulation.
abstract: Increased expression of brain-derived neurotrophic factor (BDNF) has been associated with memory-enhancing and neuroprotective properties of some drugs under chronic cerebral hypoperfusion (CCH) condition. Ginsenoside Rd (GSRd), one of the main active ingredients in Panax ginseng, is widely used for brain protection. However, it is poorly understood whether epigenetic mechanisms implied in the BDNF modulation after GSRd treatment for CCH remain elusive. Here, we investigated the neuroprotective effects of GSRd and the involved mechanisms. We demonstrated that GSRd administration ameliorated CCH-induced impairment of learning and memory behaviors, evidenced by decreased escape latency and increased number of crossing the platform in Morris water maze test. This improvement was associated with promoted neuron survival and increased BDNF expression in the hippocampus and prefrontal cortex of CCH mice. GSRd improved neuron survival and decreased neuron apoptosis and the level of caspase-3 under oxygen-glucose deprivation/reoxygenation (OGD/R) by upregulation of BDNF as well as in vitro. The levels of acetylated histone H3 (Ac-H3) and histone deacetylase (histone deacetylase 2 (HDAC2)) were altered under OGD/R in a time-dependent manner, and GSRd reestablished the balance between Ac-H3 and HDAC2 which resulted in upregulation of BDNF and increased neuron survival. MS-275, an inhibitor of class I HDACs, abolished the levels of Ac-H3 at the bdnf promoters and enhanced upregulation of BDNF after GSRd administration, suggesting a synergistic effect between GSRd and MS-275. All the data suggested that GSRd provided neuroprotection by epigenetic modulation which accounted for the regulation of BDNF in CCH mice.
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.|Department of Neurology, The 254th Hospital of PLA, Tianjin, 300142, People's Republic of China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wan
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Xue
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Neurology, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province, 710032, People's Republic of China. yumeiwu@fmmu.edu.cn.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Wu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002545:Brain Ischemia / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002908:Chronic Disease; D060825:Cognitive Dysfunction / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D044127:Epigenesis, Genetic / Q000187:drug effects; D036145:Ginsenosides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000473:pathology; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000066829:Neuroprotection / Q000187:drug effects / Q000235:genetics; D010100:Oxygen / Q000494:pharmacology; D065853:Spatial Learning / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D050882:CREB-Binding Protein; D036145:Ginsenosides; D005947:Glucose; D056464:Histone Deacetylase 2; D006657:Histones; D010100:Oxygen; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C049863:ginsenoside Rd
keywords: Brain-derived neurotrophic factor; Chronic cerebral hypoperfusion; Epigenetic; Ginsenoside Rd; HDAC2; Histone H3