title: Dehydroevodiamine•HCl Protects Against Memory Impairment and Cerebral Amyloid-&#946; Production in Tg2576 Mice by Acting as a &#946;-Secretase Inhibitor.
abstract: We previously demonstrated that dehydroevodiamine•HCl (DHED), which was purified from Evodia rutaecarpa Bentham (Rutaceae), has beneficial effects on memory impairment and neuronal damage in three disease models. To investigate the preventive action of DHED in Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory decline, amyloid-β (Aβ) protein-containing neuritic plaques and neurofibrillary tangles, in this study, we proposed that DHED may be therapeutically effective against the memory impairment and disease-related neurochemical changes that occur in Tg2576 (Tg) mice. DHED (0.5 mg/kg) was intraperitoneally administered to 7-month-old Tg and wild type mice for 4 months. In passive avoidance and water maze tests, DHED improved memory impairment of Tg mice after 4 months of administration. DHED also reduced cortical levels of soluble Aβ40, soluble Aβ42 and total Aβ peptides in the Tg mice. Additionally, we investigated whether DHED may be a β-secretase inhibitor that affects the production of Aβ related to the formation of neuritic plaques. DHED directly inhibited β-secretase activity in a concentrationdependent manner. The concentration required for 50 % enzyme inhibition (IC50) was 40.96 μM, and DHED may act as a competitive inhibitor of β-secretase. Moreover, DHED interacted strongly with BACE1 (β-secretase 2QP8), as demonstrated in the analysis of the binding mode of DHED in the active site of human BACE1. In conclusion, DHED may exhibit therapeutic effects for AD as a β-secretase inhibitor.
authors: Ki Young
authors: KY
authors: Shin
authors: Su-Jin
authors: SJ
authors: Noh
authors: Cheol Hyoung
authors: CH
authors: Park
authors: Yun Ha
authors: YH
authors: Jeong
authors: Keun-A
authors: KA
authors: Chang
authors: Jakyung
authors: J
authors: Yoo
authors: Hee Jin
authors: HJ
authors: Kim
authors: Sungji
authors: S
authors: Ha
authors: Hye-Sun
authors: HS
authors: Kim
authors: Hyun-Ju
authors: HJ
authors: Park
authors: Jun-Ho
authors: JH
authors: Lee
authors: Cheil
authors: C
authors: Moon
authors: Neuroscience Research Institute (NRI), Gachon University, Incheon, 21565, Korea. yhsuh@snu.ac.kr.
authors: Yoo-Hun
authors: YH
authors: Suh
mesh_terms: D000470:Alkaloids / Q000627:therapeutic use*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics
chemical_list: D000470:Alkaloids; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; C028633:dehydroevodiamine; D053829:Amyloid Precursor Protein Secretases