Metabolomic insights into the neuroprotective actions of Ziziphi spinosae semen and jujuboside B against Aβ-induced toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Ziziphi Spinosae Semen (ZSS), the dried seeds of Ziziphus jujuba Mill. var. spinosa has been used for over two millennia in East Asian ethnomedicine to calm the mind, nourish Yin, and relieve insomnia. Although not traditionally described as a cognition-enhancing herb, its central regulatory effects suggest potential relevance to neuroprotection, yet the underlying metabolic mechanisms remain unclear.

AIM OF THE STUDY: This study evaluated the anti-Alzheimer's disease (AD) activity of ZSS and its major constituent jujuboside B (JuB) in an Aβ1-42-induced C. elegans model, aiming to elucidate how ZSS modulates neurotransmitter metabolism and protective signaling pathways.

MATERIALS AND

METHODS

Behavioral assays, fluorescence imaging, and lifespan analysis were used to assess neuroprotection and Aβ1-42 deposition. Untargeted metabolomics profiled ZSS-induced metabolic alterations, while daf-16 and sir-2.1 mutants were applied to determine pathway involvement. In vivo quantification and targeted metabolomics were conducted to identify active compounds and characterize neurotransmitter-related metabolic modulation.

RESULTS

ZSS significantly delayed Aβ1-42-induced paralysis, reduced amyloid accumulation, and extended lifespan in nematodes. These effects depended on daf-16 and sir-2.1. Metabolomics revealed extensive regulation of amino acid and neurotransmitter pathways, including GABA, glutamate, and tryptophan metabolism. JuB was identified as the primary absorbed compound and restored neurotransmitter homeostasis while reprogramming multiple metabolic pathways associated with dopaminergic and glutamatergic signaling.

CONCLUSIONS

ZSS and JuB exert multi-target anti-AD effects by rebalancing neurotransmitters, modulating metabolic networks, and activating protective genetic pathways, supporting their potential as functional food-derived candidates for mitigating Aβ1-42-induced neurotoxicity.