Ethyl Acetate Fraction of Zanthoxylum bungeanum Ameliorates Cognitive Deficit by Facilitating the PHGDH-Dependent Astrocyte-Neuron Serine Shuttle in Aging Mice

  • J Agric Food Chem. 2025 Jul 2;73(26):16301-16316. doi: 10.1021/acs.jafc.4c12077.
Meihuan Zhao  1  2  3 ,  Li Zeng  1  2  3 ,  Yongtao Zhou  1  2  3 ,  Chuan Yang  1  2  3 ,  Ruilin Sheng  1  2  3 ,  Xiao Liu  1  2  3 ,  Wen Wen  1  2  3 ,  Simin Yang  3  4 ,  Shiqi Zhang  1  2  3 ,  Shijun Xu  1  2  3
Affiliations
  • 1. State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
  • 2. School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
  • 3. Institute of Material Medica Integration and Transformation for Brain Disorders, Chengdu University traditional Chinese medicine, Chengdu 611137, PR China.
  • 4. School of Health Preservation and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
PMID: 40537930 DOI: 10.1021/acs.jafc.4c12077
Abstract

Enhancing the astrocyte-neuron serine shuttle to maintain N-methyl-d-aspartate receptor (NMDARs)-mediated neuronal synaptic plasticity is an effective strategy to alleviate age-related cognitive deficit (ARCD). This study investigated the mechanisms by which the ethyl acetate extract of Zanthoxylum bungeanum Maxim. (EA), a famous spiceberry, attenuates ARCD by established aging mice and the coculture system of U87 and SH-SY5Y cells model using d-galactose stimulation. Results display that EA significantly elevated the astrocyte-neuron serine shuttle and activated the NMDARs/calmodulin-dependent kinase II (CaMKII) pathway. Moreover, EA markedly enhanced glycolytic flux in the brain of aging mice and U87 cells, evidenced by the elevated enzymatic activities of Hexokinase (HK), 6-phosphofructokinase (PFK), and Pyruvate Kinase (PK), increased adenosine triphosphate (ATP), lactate-to-pyruvate ratio, pyruvate contents, and lactate release. Furthermore, EA significantly alleviated synaptic morphology and elevated synuclein (SYN), postsynaptic density protein 95 (PSD95), and microtubule-associated protein-2 (MAP2) protein levels. Interestingly, NCT503, a phosphoglycerate dehydrogenase (PHGDH) inhibitor, reversed these effects of EA. Finally, EA markedly reduced neuropathological impairment and cognitive impairment in aging mice. The study confirmed that EA promoted astrocytic PHGDH-mediated l-serine production and the astrocyte-neuron serine shuttle to activate the NMDARs/CaMKII pathway in neurons to relieve ARCD.

Keywords
Zanthoxylum bungeanum Maxim.; age-related cognitive deficits; glycolysis; l-serine; serine shuttle.
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