Jujuboside B

The interaction between the cardiovascular and brain is crucial for epileptogenesis, but the underlying mechanisms are unclear. Ziziphi Spinosae Semen (ZSS), a traditional herb used for its heart-nourishing and mind-calming effects, is hypothesized to potentially suppress seizures through modulation of cardiovascular function.

To explore how jujuboside B (JuB) from ZSS affects epilepsy through cardiovascular-brain crosstalk.

In acute seizure models, epileptic activity and cardiovascular parameters were evaluated via Electroencephalogram/ Electromyography (EEG/EMG) recording, multiphysiological signal monitoring, laser speckle blood flow imaging, and left vagotomy. Whole-brain c-Fos mapping revealed that nucleus of the solitary tract (NTS) was an activated region. Chemogenetic methods and in vivo multi-channel recording techniques were used to activate neurons expressing vesicular glutamate transporter 2 in NTS (NTS-VGLUT2⁺) neurons and monitor neuronal activity in the dentate gyrus (DG).

JuB exerts both hypotensive and antiseizure effects. Sodium nitroprusside (SNP) elicited similar effects, establishing a therapeutic link between blood pressure reduction and seizure suppression. JuB increased vagal nerve discharge, and its antiseizure activity was abolished by left vagotomy. Whole-brain c-Fos mapping identified NTS and DG as key responsive regions. JuB selectively activated NTS-VGLUT2⁺ neurons, augmenting their firing. Chemogenetic activation of these neurons inhibited DG neuronal hyperactivity and suppressed pentylenetetrazole (PTZ)-induced seizures.

JuB exerts its antiseizure effect through the activation of vagal-mediated NTS-VGLUT2⁺ neurons and the inhibition of DG neurons. This reconciles cardiovascular and neurological modulation. These findings elucidate JuB's pharmacological basis, advance epileptic pathophysiology understanding, and support personalized therapeutic strategies for epilepsy with hypertension.

Ziziphi Spinosae Semen (ZSS), the dried mature seed of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H.F. Chou, is a classic traditional Chinese medicine (TCM) with a clinical application history of over two millennia. The host plant is mainly distributed in the tropical and subtropical regions of Asia and America. It was first recorded in Shen Nong's Herbal Classic; in TCM theory, ZSS is characterized by a sweet and sour taste, a neutral nature, and tropism for the Liver, Gallbladder, and Heart Meridians, and possesses the effects of nourishing the heart and replenishing the liver, calming the mind and tranquilizing the spirit, astringing sweating, and promoting the production of body fluids. These traditional applications provide a crucial foundation and direction for ethnopharmacological research.

The botanical characteristics, traditional and modern clinical applications, phytochemistry, pharmacological activity, and quality marker (Q-marker) prediction of ZSS are reviewed. It aims to address the limitations of traditional quality control and achieve the transition from "single-component detection" to "association with overall efficacy".

Available publications about ZSS were collected by searching library and electronic databases, including PubMed, CNKI, Web of Science, Google Scholar, relevant TCM journals, and classic works.

Modern phytochemical and pharmacological studies show that ZSS contains 155 components, including terpenoids, steroids, flavonoids, alkaloids, fatty acids and volatile oils, and other constituents. Among these compounds, triterpenoid jujuboside A and flavonoid spinosin have attracted widespread attention for their diverse pharmacological activities, while other components in ZSS also contribute to its efficacy by exerting sedative and hypnotic, anti-anxiety, anti-Alzheimer's disease, and cardioprotective effects by regulating neurotransmitters, other neural pathways, and the intestinal flora. Through Q-marker predictive analysis revealed that jujuboside A, jujuboside B, spinosin, and 6‴-feruloylspinosin from ZSS are potential Q-markers.

Although ZSS has therapeutic potential, the current quality control standards for ZSS are still insufficient. The Chinese Pharmacopoeia (2025 Edition) only relies on the quantification of jujuboside A and spinosin, failing to reflect their overall quality-this is an important limitation of the multi-component synergy principle of TCM. To address this gap, a novel predictive Q-marker model is proposed to integrate multi-dimensional data and establish a powerful and scientific quality assessment framework. By prioritizing bioactive ingredients with traceable efficacy and utilizing advanced analytical techniques, this work advances the standardization of ZSS, highlighting its significance for the modernization of TCM and evidence-based clinical applications.