Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer’s Disease
Alzheimer’s disease (AD) is the main type of dementia and is characterized by progressive memory loss and a notable decrease in cholinergic neuron activity. As classic drugs currently used in the clinic, acetylcholinesterase inhibitors (AChEIs) restore acetylcholine levels and relieve the symptoms o...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnagi.2019.00003/full |
| _version_ | 1831740088286969856 |
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| author | Yu Wang Jia Xia Mengjun Shen Yifan Zhou Zhe Wu Yuhuan Shi Jianrong Xu Lina Hou Rui Zhang Zhuibai Qiu Qiong Xie Hongzhuan Chen Yongfang Zhang Hao Wang |
| author_facet | Yu Wang Jia Xia Mengjun Shen Yifan Zhou Zhe Wu Yuhuan Shi Jianrong Xu Lina Hou Rui Zhang Zhuibai Qiu Qiong Xie Hongzhuan Chen Yongfang Zhang Hao Wang |
| author_sort | Yu Wang |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the main type of dementia and is characterized by progressive memory loss and a notable decrease in cholinergic neuron activity. As classic drugs currently used in the clinic, acetylcholinesterase inhibitors (AChEIs) restore acetylcholine levels and relieve the symptoms of AD, but are insufficient at delaying the onset of AD. Based on the multi-target-directed ligand (MTDL) strategy, bis-(-)-nor-meptazinol (BIS-MEP) was developed as a multi-target AChEI that mainly targets AChE catalysis and the β-amyloid (Aβ) aggregation process. In this study, we bilaterally injected Aβ oligomers and ibotenic acid (IBO) into the hippocampus of ICR mice and then subcutaneously injected mice with BIS-MEP to investigate its therapeutic effects and underlying mechanisms. According to the results from the Morris water maze test, BIS-MEP significantly improved the spatial learning and memory impairments in AD model mice. Compared with the vehicle control, the BIS-MEP treatment obviously inhibited the AChE activity in the mouse brain, consistent with the findings from the behavioral tests. The BIS-MEP treatment also significantly reduced the Aβ plaque area in both the hippocampus and cortex, suggesting that BIS-MEP represents a direct intervention for AD pathology. Additionally, the immunohistochemistry and ELISA results revealed that microglia (ionized calcium-binding adapter molecule 1, IBA1) and astrocyte (Glial fibrillary acidic protein, GFAP) activation and the secretion of relevant inflammatory factors (TNFα and IL-6) induced by Aβ were decreased by the BIS-MEP treatment. Furthermore, BIS-MEP showed more advantages than donepezil (an approved AChEI) as an Aβ intervention. Based on our findings, BIS-MEP improved spatial learning and memory deficits in AD mice by regulating acetylcholinesterase activity, Aβ deposition and the inflammatory response in the brain. |
| first_indexed | 2024-12-21T13:50:58Z |
| format | Article |
| id | doaj.art-d8734d9f67c5414c97cf735bbf5adace |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-21T13:50:58Z |
| publishDate | 2019-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-d8734d9f67c5414c97cf735bbf5adace2022-12-21T19:01:42ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652019-01-011110.3389/fnagi.2019.00003416317Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer’s DiseaseYu Wang0Jia Xia1Mengjun Shen2Yifan Zhou3Zhe Wu4Yuhuan Shi5Jianrong Xu6Lina Hou7Rui Zhang8Zhuibai Qiu9Qiong Xie10Hongzhuan Chen11Yongfang Zhang12Hao Wang13Department of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaDepartment of Pharmacology and Chemical Biology, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaAlzheimer’s disease (AD) is the main type of dementia and is characterized by progressive memory loss and a notable decrease in cholinergic neuron activity. As classic drugs currently used in the clinic, acetylcholinesterase inhibitors (AChEIs) restore acetylcholine levels and relieve the symptoms of AD, but are insufficient at delaying the onset of AD. Based on the multi-target-directed ligand (MTDL) strategy, bis-(-)-nor-meptazinol (BIS-MEP) was developed as a multi-target AChEI that mainly targets AChE catalysis and the β-amyloid (Aβ) aggregation process. In this study, we bilaterally injected Aβ oligomers and ibotenic acid (IBO) into the hippocampus of ICR mice and then subcutaneously injected mice with BIS-MEP to investigate its therapeutic effects and underlying mechanisms. According to the results from the Morris water maze test, BIS-MEP significantly improved the spatial learning and memory impairments in AD model mice. Compared with the vehicle control, the BIS-MEP treatment obviously inhibited the AChE activity in the mouse brain, consistent with the findings from the behavioral tests. The BIS-MEP treatment also significantly reduced the Aβ plaque area in both the hippocampus and cortex, suggesting that BIS-MEP represents a direct intervention for AD pathology. Additionally, the immunohistochemistry and ELISA results revealed that microglia (ionized calcium-binding adapter molecule 1, IBA1) and astrocyte (Glial fibrillary acidic protein, GFAP) activation and the secretion of relevant inflammatory factors (TNFα and IL-6) induced by Aβ were decreased by the BIS-MEP treatment. Furthermore, BIS-MEP showed more advantages than donepezil (an approved AChEI) as an Aβ intervention. Based on our findings, BIS-MEP improved spatial learning and memory deficits in AD mice by regulating acetylcholinesterase activity, Aβ deposition and the inflammatory response in the brain.https://www.frontiersin.org/article/10.3389/fnagi.2019.00003/fullAlzheimer’s diseaseacetylcholinesterase inhibitorBIS-MEPβ-amyloid peptidelearningmemory |
| spellingShingle | Yu Wang Jia Xia Mengjun Shen Yifan Zhou Zhe Wu Yuhuan Shi Jianrong Xu Lina Hou Rui Zhang Zhuibai Qiu Qiong Xie Hongzhuan Chen Yongfang Zhang Hao Wang Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer’s Disease Frontiers in Aging Neuroscience Alzheimer’s disease acetylcholinesterase inhibitor BIS-MEP β-amyloid peptide learning memory |
| title | Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer’s Disease |
| title_full | Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer’s Disease |
| title_fullStr | Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer’s Disease |
| title_full_unstemmed | Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer’s Disease |
| title_short | Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of β-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer’s Disease |
| title_sort | effects of bis mep on reversing amyloid plaque deposition and spatial learning and memory impairments in a mouse model of β amyloid peptide and ibotenic acid induced alzheimer s disease |
| topic | Alzheimer’s disease acetylcholinesterase inhibitor BIS-MEP β-amyloid peptide learning memory |
| url | https://www.frontiersin.org/article/10.3389/fnagi.2019.00003/full |
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