Flavonoid-Like Components of Peanut Stem and Leaf Extract Promote Sleep by Decreasing Neuronal Excitability

Scope: Peanut stem and leaf (PSL), a traditional Chinese medicine, is widely used as a dietary supplement to improve sleep quality; however, the underlying mechanism is unclear. Here, the study aims to determine whether active compounds in PSL extract exert their effects by mediating neuronal excitability. Methods and Results: Aqueous PSL extract (500 mg kg⁻¹ BW) increases the duration of total sleep (TS), slow wave sleep (SWS) and rapid eye movement sleep (REMS) in BALB/c mice after 7 and 14 continuous days of intragastric administration. Two PSL extract components with flavonoid-like structures: 4',7-di-O-methylnaringenin (DMN, 61 µg kg⁻¹ BW) and 2’-O-methylisoliquiritigenin (MIL, 12 µg kg⁻¹ BW), show similar effects on sleep in BALB/c mice. Moreover, incubation with DMN (50 µM) and MIL (50 µM) acutely reduces voltage-gated sodium and potassium currents and suppresses the firing of evoked action potential in mouse cortical neurons, indicating the inhibition on neuronal excitability. Meanwhile, RNA-seq analysis predicts the potential regulation of voltage-gated channels, which is according with the molecular docking simulation that both MIL and DMN can bind to voltage gated sodium channels 1.2 (Na_v1.2). Conclusions: DMN and MIL are the active ingredients of PSL that improve sleep quality, suggesting that PSL promotes sleep by regulating the excitability of neurons.