Qiuhong Wang1, Changfu Wang2, Zunpeng Shu2, Kelvin Chan3, Shuming Huang4, Yan Li2, Yang Xiao2, Lihua Wu2, Haixue Kuang2, Xiaobo Sun5. 1. 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. 2. Key Laboratory of Chinese Materia Medica (Ministry of Education), Heilongjiang University of Chinese Medicine, Harbin, China. 3. Centre for Complementary Medicine Research, University of Western Sydney, NSW 2560, Australia; Faculty of Pharmacy, The University of Sydney, NSW 2006, Australia. 4. 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. 5. Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: xbsun@implad.ac.cn.
Abstract
ETHNOPHAMACOLOGICAL RELEVANCE: 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. MATERIALS AND 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. CONCLUSION: 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.
ETHNOPHAMACOLOGICAL RELEVANCE: 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. MATERIALS AND 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. CONCLUSION: 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: Gitishree Das; Han-Seung Shin; Rosa Tundis; Sandra Gonçalves; Ourlad Alzeus G Tantengco; Maria G Campos; Rosaria Acquaviva; Giuseppe Antonio Malfa; Anabela Romano; Joyce Ann H Robles; Mariel Q Clores; Jayanta-Kumar Patra Journal: Plants (Basel) Date: 2021-04-22
Authors: Lu-Da Feng; Yang Tian; Xin Wang; Run Dai; Song Cai; Yu-Jia Cao; Yin-Chu Si Journal: Evid Based Complement Alternat Med Date: 2018-09-12 Impact factor: 2.629