Alpha-asarone improves cognitive function of aged rats by alleviating neuronal excitotoxicity via GABA A receptors

Alzheimer's disease (AD), the most common form of dementia, still lacks effective treatment at present. Alpha-asarone (ASA) is the major compound isolated from the Chinese medicinal herb Acorus gramineus. It has been reported to enhance cognitive function in rodent models, yet its mechanism was...

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Published in:Neuropharmacology 2020-01, Vol.162, p.107843
Main Authors: Chen, Yu, Gao, Xiaofeng, Liu, Qi, Zeng, Lili, Zhang, Kun, Mu, Keman, Zhang, Di, Zou, Huixi, Wu, Nan, Ou, Jierui, Wang, Qiantao, Mao, Shengjun
Format: Article
Language:English
Subjects:
Aging - metabolism
Aging - psychology
Allosteric Regulation
Amyloid beta-Peptides - drug effects
Amyloid beta-Peptides - metabolism
Animals
Anisoles - pharmacology
Calcium - metabolism
Cognition - drug effects
Glutamic Acid - metabolism
Hippocampus - cytology
Hippocampus - drug effects
Hippocampus - metabolism
Molecular Docking Simulation
Molecular Dynamics Simulation
Neurons - drug effects
Neurons - metabolism
Neuroprotective Agents - pharmacology
Patch-Clamp Techniques
Peptide Fragments - drug effects
Peptide Fragments - metabolism
Rats
Receptors, GABA-A - drug effects
Receptors, GABA-A - metabolism
Spatial Memory - drug effects
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Summary:Alzheimer's disease (AD), the most common form of dementia, still lacks effective treatment at present. Alpha-asarone (ASA) is the major compound isolated from the Chinese medicinal herb Acorus gramineus. It has been reported to enhance cognitive function in rodent models, yet its mechanism was not fully understood. In this work, we demonstrated that ASA improved the spatial memory, reduced the neuronal injury, and decreased the level of Aβ in the hippocampus of aged rats. The results also showed that ASA had the neuroprotective effects against glutamate toxicity and decreased cytoplasmic calcium level in primary hippocampal neurons. By comparing the multiple properties of ASA and propofol (PPF) via computer modelling, we speculated that ASA may bind to the PPF binding site of type A gamma (γ)-aminobutyric acid receptors (GABA Rs). This was further supported by the whole-cell patch-clamp recording. Our results suggested that ASA, as a GABA R positive allosteric modulator (PAM), can improve cognitive function of aged rats by alleviating the neuronal overexcitation. Furthermore, the binding mode of ASA on GABA R may lay a foundation for structure-based drug design in AD therapy.
ISSN:1873-7064
DOI:10.1016/j.neuropharm.2019.107843