Dehydroevodiamine•HCl Protects Against Memory Impairment and Cerebral Amyloid-β Production in Tg2576 Mice by Acting as a β-Secretase Inhibitor

Title:Dehydroevodiamine•HCl Protects Against Memory Impairment and Cerebral Amyloid-β Production in Tg2576 Mice by Acting as a β-Secretase Inhibitor

Volume: 15 Issue: 8

Author(s): Ki Young Shin, Su-Jin Noh, Cheol Hyoung Park, Yun Ha Jeong, Keun-A Chang, Jakyung Yoo, Hee Jin Kim, Sungji Ha, Hye-Sun Kim, Hyun-Ju Park, Jun-Ho Lee, Cheil Moon and Yoo-Hun Suh

Affiliation:

Keywords: Alzheimer’s disease, dehydroevodiamine•HCl, memory, β-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.

Cite this article as:

Shin Young Ki, Noh Su-Jin, Park Hyoung Cheol, Jeong Ha Yun, Chang Keun-A, Yoo Jakyung, Kim Jin Hee, Ha Sungji, Kim Hye-Sun, Park Hyun-Ju, Lee Jun-Ho, Moon Cheil and Suh Yoo-Hun, Dehydroevodiamine•HCl Protects Against Memory Impairment and Cerebral Amyloid-β Production in Tg2576 Mice by Acting as a β-Secretase Inhibitor, CNS & Neurological Disorders - Drug Targets 2016; 15 (8) . https://dx.doi.org/10.2174/1871527315666160815163723