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 not fully understood. In this work, we demonstrated that ASA improved the spatial memory, reduced the neuronal injury, and decreased the level of Aβ_1-42 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_ARs). This was further supported by the whole-cell patch-clamp recording. Our results suggested that ASA, as a GABA_AR positive allosteric modulator (PAM), can improve cognitive function of aged rats by alleviating the neuronal overexcitation. Furthermore, the binding mode of ASA on GABA_AR may lay a foundation for structure-based drug design in AD therapy.