title: Valeriana amurensis improves Amyloid-beta 1-42 induced cognitive deficit by enhancing cerebral cholinergic function and protecting the brain neurons from apoptosis in mice.
abstract: BACKGROUND
  Valeriana amurensis, a perennial medicinal herb, has been widely used as anxiolytic, antidepressant, antispasmodic, and sedative in traditional Chinese medicines (TCMs). Moreover, it has been used to treat dementia in Mongolia preparations. In our previous study, we reported that AD-effective fraction of Valeriana amurensis (AD-EFV) has protective effect on Aβ-induced toxicity in PC12 cells. Up to now, however, the therapeutic effect of Valeriana amurensis on Alzheimer disease (AD) has not been explored. This study was designed to determine whether the AD-EFV could improve the Amyloid-beta (Aβ)-induced cognitive deficit and to explore the mechanism of AD-EFV improves cognitive deficit in intact animals.
  
  
  METHODS
  The constituents of AD-EFV were isolated with silica gel, octadecyl silica gel (ODS) column chromatography (CC) and preparative HPLC. The structures of compounds were determined by detailed NMR and ESI-MS data analyses. AD mice model was established by injecting A(β1-42) (1 μL, 200 μmol) into the bilateral ventricle. Cognitive performance was evaluated by the Morris water maze (MWM) test. The level of cerebral acetylcholine (ACh), the activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were investigated using Enzyme-linked immunoassay (ELISA) kits. Brain sections were processed and neuronal apoptosis in hippocampus were evaluated by Hematoxylin and Eosin (HE), Nissl, and Tunel stainings. The analyses of p-ERK/ERK and Bcl-2/Bax protein expression by western blot assay were used to explore the anti-neuronal apoptosis mechanism of AD-EFV.
  
  
  RESULTS
  Seventeen compounds (15 lignans and two iridoids) were isolated from AD-EFV. A significant improvement in cognitive function was observed in administrated AD-EFV AD model mice. AD-EFV increased the ACh level by enhancing the ChAT activity but has no effect on AChE activity in the cerebral cortex and hippocampus in mice. Moreover, the histological injury in hippocampus CA1 induced by A(β1-42) was inhibited following administration of the AD-EFV. As well as the expression ratios of Bcl-2 to Bax and p-ERK to ERK were increased significantly in the mice which were administrated AD-EFV.
  
  
  CONCLUSIONS
  These findings suggest that AD-EFV could ameliorate Aβ induced cognitive dysfunction through two underlying mechanisms: AD-EFV enhances the cerebral cholinergic function by increasing the secretion of ACh and enhancing the ChAT activity, and AD-EFV protects the brain neurons from Aβ induced apoptosis via activating the p-ERK and Bcl-2 signaling and suppressing the Bax pathways. Besides, the main constituents of AD-EFV are lignans which might be responsible for the AD-activity of Valeriana amurensis.
authors.affiliation: Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, China.
authors.forename: Changfu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, China.
authors.forename: Zunpeng
authors.initials: Z
authors.lastname: Shu
authors.affiliation: Centre for Complementary Medicine Research, University of Western Sydney, NSW 2560, Australia; Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Chan
authors.affiliation: Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Centre for Complementary Medicine Research, University of Western Sydney, NSW 2560, Australia; Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia.
authors.forename: Shuming
authors.initials: S
authors.lastname: Huang
authors.affiliation: Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wu
authors.affiliation: Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, China.
authors.forename: Haixue
authors.initials: H
authors.lastname: Kuang
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: xbsun@implad.ac.cn.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Sun
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D059329:Cholinergic Neurons / Q000187:drug effects* / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000633:toxicity*; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D018517:Plant Roots; D011897:Random Allocation; D027343:Rhizome; D014632:Valerian
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010936:Plant Extracts; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Amyloid-beta; Cholinergic function; Cognitive deficit; Valeriana amurensis