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A Novel, Multi-Target Natural Drug Candidate, Matrine, Improves Cognitive Deficits in Alzheimer’s Disease Transgenic Mice by Inhibiting Aβ Aggregation and Blocking the RAGE/Aβ Axis

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Abstract

The treatment of AD is a topic that has puzzled researchers for many years. Current mainstream theories still consider Aβ to be the most important target for the cure of AD. In this study, we attempted to explore multiple targets for AD treatments with the aim of identifying a qualified compound that could both inhibit the aggregation of Aβ and block the RAGE/Aβ axis. We believed that a compound that targets both Aβ and RAGE may be a feasible strategy for AD treatment. A novel and small natural compound, Matrine (Mat), was identified by high-throughput screening of the main components of traditional Chinese herbs used to treat dementia. Various experimental techniques were used to evaluate the effect of Mat on these two targets both in vitro and in AD mouse model. Mat could inhibit Aβ42-induced cytotoxicity and suppress the Aβ/RAGE signaling pathway in vitro. Additionally, the results of in vivo evaluations of the effects of Mat on the two targets were consistent with the results of our in vitro studies. Furthermore, Mat reduced proinflammatory cytokines and Aβ deposition and attenuated the memory deficits of AD transgenic mice. We believe that this novel, multi-target strategy to inhibit both Aβ and RAGE, is worthy of further exploration. Therefore, our future studies will focus on identifying even more effective multi-target compounds for the treatment of AD based on the molecular structure of Mat.

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Acknowledgments

Support for this work includes funding from the National Nature Science Foundation of China (81271214, 31171219, and 81401061), the Natural Science Foundation of Guangdong Province (S2013040013740), The key cultivation project of Guangdong Province (4CX14092G), Medical Scientific Research Foundation of Guangdong Province (B2013306), and the Research foundation for the construction of Traditional Chinese medicine of Guangdong Province (20131257).

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    1. Guangdong key laboratory of age-related cardiac and cerebral diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province, China

      Lili Cui, Yujie Cai, Wanwen Cheng, Gen Liu, Jianghao Zhao, Hua Tao, Mingkang Yin, Tingting Liu, Yu Liu, Pengru Huang, Zhou Liu, Keshen Li & Bin Zhao

    2. Institutes of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China

      Jianghao Zhao & Hua Tao

    3. Departments of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China

      Hao Cao

    4. Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People’s Republic of China

      Yan Wang

    5. Institute of clinical medicine, Jinan University, Guangzhou, People’s Republic of China

      Keshen Li

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    Lili Cui, Yujie Cai and Wanwen Cheng contributed equally to this work.

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    Cui, L., Cai, Y., Cheng, W. et al. A Novel, Multi-Target Natural Drug Candidate, Matrine, Improves Cognitive Deficits in Alzheimer’s Disease Transgenic Mice by Inhibiting Aβ Aggregation and Blocking the RAGE/Aβ Axis. Mol Neurobiol 54, 1939–1952 (2017). https://doi.org/10.1007/s12035-016-9783-8

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