Anemoside A3 Enhances Cognition Through the Regulation of Synaptic Function and Neuroprotection Open

Original Article

 http://www.nature.com/npp/journal/vaop/naam/abs/npp201537a.html

Neuropsychopharmacology accepted article preview 4 February 2015; doi: 10.1038/npp.2015.37

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Anemoside A3 Enhances Cognition Through the Regulation of Synaptic Function and Neuroprotection
Open

Fanny C F Ip^1,2,3,4,7, Wing-Yu Fu^1,2,3,7, Elaine Y L Cheng^1,2,3, Estella P S Tong^1,2,3, Ka-Chun Lok^1,2,3, Yan Liang^1,2,3, Wen-Cai Ye^4,5,6,8 and Nancy Y Ip^1,2,3,4,8

1. ¹Division of Life Science, Hong Kong, China
2. ²Molecular Neuroscience Center, Hong Kong, China
3. ³State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China
4. ⁴HKUST–Jinan Joint Laboratory of Innovative Drug Discovery, Jinan University, Guangzhou, China
5. ⁵Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Guangzhou, China
6. ⁶Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Guangzhou, China

Correspondence: Professor NY Ip, Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China, Tel: 852 2358 7269, Fax: 852 2358 1464, E-mail: BOIP@UST.HK; Professor W-C Ye, Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China, Tel: 8620 8522 0936, Fax: 8620 8522 1559, E-mail: CHYWC@YAHOO.COM.CN

⁷These authors Contributed equally to this work

⁸Co-corresponding authors

Received 23 September 2014; Revised 16 January 2015; Accepted 21 January 2015
Accepted article preview online 4 February 2015

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Abstract

Compounds that have the ability to both strengthen synaptic function and facilitate neuroprotection are valuable cognitive enhancers that may improve health and quality of life as well as retard age-related cognitive deterioration. Medicinal plants are an abundant source of potential cognitive enhancers. Here, we report that anemoside A3 (AA3) isolated from Pulsatilla chinensis modulates synaptic connectivity in circuits central to memory enhancement. AA3 specifically modulates the function of AMPA-type glutamate receptors (AMPARs) by increasing serine phosphorylation within the GluA1 subunit, which is a modification required for the trafficking of GluA1-containing AMPARs to synapses. Furthermore, AA3 administration activates several synaptic signaling molecules and increases protein expressions of the neurotrophin brain-derived neurotrophic factor (BDNF) and monoamine neurotransmitters in the mouse hippocampus. In addition to acting through AMPARs, AA3 also acts as a noncompetitive NMDA receptor (NMDAR) modulator with a neuroprotective capacity against ischemic brain injury and over-excitation in rats. These findings collectively suggest that AA3 possesses a unique ability to modulate the functions of both AMPARs and NMDARs. Concordantly, behavioral studies indicate that AA3 not only facilitates hippocampal long-term potentiation, but also enhances spatial reference memory formation in mice. These multifaceted roles suggest that AA3 is an attractive candidate for further development as a cognitive enhancer capable of alleviating memory dysfunctions associated with aging and neurodegenerative diseases.