The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect

  • Pharmacol Ther. 2016 Jun;162:179-87. doi: 10.1016/j.pharmthera.2016.01.002.
Shifeng Chu  1 ,  Shaolin Liu  2 ,  Wenzhen Duan  3 ,  Yong Cheng  4 ,  Xueying Jiang  5 ,  Chuanjiang Zhu  4 ,  Kang Tang  6 ,  Runsheng Wang  7 ,  Lin Xu  8 ,  Xiaoying Wang  9 ,  Xiaoming Yu  4 ,  Kemei Wu  4 ,  Yan Wang  4 ,  Muzou Wang  4 ,  Huiyong Huang  10 ,  Juntian Zhang  11
Affiliations
  • 1. 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.
  • 2. Department of Anatomy & Neurobiology and Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • 3. 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.
  • 4. Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 5. National Institute of Mental Health, Bethesda, MD 20892, USA.
  • 6. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 7. MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
  • 8. Franciscan Hospital for Children, Brighton, MA 02135, USA.
  • 9. Research Center for Pharmacology and Toxicity, Chinese Academy of Medical Science & Peking Union Medical College, Institute of Medicinal Plant Development, Beijing 100193, China.
  • 10. Key Laboratory of Diagnostics of Traditional Chinese Medicine, Collaborative Innovation Center of Digital Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China.
  • 11. Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
PMID: 26812265 DOI: 10.1016/j.pharmthera.2016.01.002
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.

Keywords
Calcium; Chirality; Clausenamide; Dementia; Long-term potentiation; Signaling pathway.
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