TY - JOUR
T1 - The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect
AU - Chu, Shifeng
AU - Liu, Shaolin
AU - Duan, Wenzhen
AU - Cheng, Yong
AU - Jiang, Xueying
AU - Zhu, Chuanjiang
AU - Tang, Kang
AU - Wang, Runsheng
AU - Xu, Lin
AU - Wang, Xiaoying
AU - Yu, Xiaoming
AU - Wu, Kemei
AU - Wang, Yan
AU - Wang, Muzou
AU - Huang, Huiyong
AU - Zhang, Juntian
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China ( 3080152730973887 and U0832008 ) and the National Key Major Item ( 2008ZX09101-015 ).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single-target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-clau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca2+ concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca2+ overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases.
AB - Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single-target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-clau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca2+ concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca2+ overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases.
KW - Calcium
KW - Chirality
KW - Clausenamide
KW - Dementia
KW - Long-term potentiation
KW - Signaling pathway
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U2 - 10.1016/j.pharmthera.2016.01.002
DO - 10.1016/j.pharmthera.2016.01.002
M3 - Review article
C2 - 26812265
AN - SCOPUS:84961141577
SN - 0163-7258
VL - 162
SP - 179
EP - 187
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
ER -