title: The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect.
abstract: 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 Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China; Key Laboratory of Diagnostics of Traditional Chinese Medicine, Collaborative Innovation Center of Digital Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Chu
authors.affiliation: Department of Anatomy & Neurobiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Shaolin
authors.initials: S
authors.lastname: Liu
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: National Institute of Mental Health, Bethesda, MD 20892, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Chuanjiang
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Kang
authors.initials: K
authors.lastname: Tang
authors.affiliation: MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
authors.forename: Runsheng
authors.initials: R
authors.lastname: Wang
authors.affiliation: Franciscan Hospital for Children, Brighton, MA 02135, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Research Center for Pharmacology and Toxicity, Chinese Academy of Medical Science & Peking Union Medical College, Institute of Medicinal Plant Development, Beijing 100193, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yu
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Kemei
authors.initials: K
authors.lastname: Wu
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Muzou
authors.initials: M
authors.lastname: Wang
authors.affiliation: Key Laboratory of Diagnostics of Traditional Chinese Medicine, Collaborative Innovation Center of Digital Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China.
authors.forename: Huiyong
authors.initials: H
authors.lastname: Huang
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: zhangjt@imm.ac.cn.
authors.forename: Juntian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D003704:Dementia / Q000188:drug therapy*; D006801:Humans; D007769:Lactams / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D017705:Lignans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D008516:Medicine, Chinese Traditional; D008569:Memory Disorders / Q000188:drug therapy
chemical_list: D007769:Lactams; D017705:Lignans; C053048:clausenamide
keywords: Calcium; Chirality; Clausenamide; Dementia; Long-term potentiation; Signaling pathway