2. Academic Validation
  3. The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect

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

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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