Apigenin promotes neuronal norepinephrine release via GPR30/PLCβ1-Ca2+-Syt1 signaling to enhance astrocytic lactate and exert neuroprotection in D-galactose-induced cognitive impairment
- 1State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine
Abstract
Objective: AD, a prevalent neurodegenerative disorder clinically defined by progressive cognitive impairment, is pathologically featured by early dysfunction of the locus coeruleus, depletion of noradrenergic (NE) neurons, and dysregulated astrocytic glycogen metabolism, which collectively compromise patients’ daily functioning. Although Api, a common phytoestrogen, has shown therapeutic efficacy in diverse diseases, its role and mechanism in AD remain unexplored.
Methods: To address this gap, we evaluated the protective effects of Api against D-gal-induced cognitive deficits through behavioral and histomorphological assessments. Untargeted metabolomics was performed to profile metabolic alterations in the locus coeruleus (LC), complemented by targeted metabolomics focusing on specific pathways. Putative targets were predicted by molecular docking and verified via cellular thermal shift assay (CETSA), while molecular biology approaches were adopted to elucidate the underlying signaling cascades.
Results: Api significantly ameliorated D-gal-induced cognitive impairment and increased hippocampal NE and lactate levels with enhanced neuronal activity. Metabolomics indicated that Api regulates energy metabolism pathways including TCA cycle, amino acid metabolism, glycolysis/gluconeogenesis, and glutathione metabolism. Specifically, Api elevated NE and lactate in the LC. GPR30 was identified and validated as the key target via molecular docking and CETSA, showing strong binding affinity. Mechanistically, Api activates GPR30 on noradrenergic neurons to regulate PLCβ1-Ca ²⁺ -Syt1 signaling, promoting NE release, which in turn drives astrocytic glycogenolysis and lactate production, thereby relieving neuronal energy deficits.
Conclusion: Collectively, this study not only clarifies the PLCβ1-Ca ²⁺ -Syt1-dependent mechanism of Api in aging-related cognitive impairment, but also highlights NE and lactate elevation as a promising therapeutic approach.
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BibTeX
@article{jiang2026apigenin,
title = {{Apigenin promotes neuronal norepinephrine release via GPR30/PLCβ1-Ca2+-Syt1 signaling to enhance astrocytic lactate and exert neuroprotection in D-galactose-induced cognitive impairment}},
author = {Shan Jiang and Ling Kong and Xueke Bai and Meng Yang and Jiaxin Ding and Yaoai Wang and Wenjing Fan and Yan Yan and Chengyu Pu and Ning Zhang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1979963},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1979963/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Apigenin promotes neuronal norepinephrine release via GPR30/PLCβ1-Ca2+-Syt1 signaling to enhance astrocytic lactate and exert neuroprotection in D-galactose-induced cognitive impairment
AU - Shan Jiang
AU - Ling Kong
AU - Xueke Bai
AU - Meng Yang
AU - Jiaxin Ding
AU - Yaoai Wang
AU - Wenjing Fan
AU - Yan Yan
AU - Chengyu Pu
AU - Ning Zhang
PY - 2026
DA - 2026/10/26
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1979963
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1979963/full
AB - Objective: AD, a prevalent neurodegenerative disorder clinically defined by progressive cognitive impairment, is pathologically featured by early dysfunction of the locus coeruleus, depletion of noradrenergic (NE) neurons, and dysregulated astrocytic glycogen metabolism, which collectively compromise patients’ daily functioning. Although Api, a common phytoestrogen, has shown therapeutic efficacy in diverse diseases, its role and mechanism in AD remain unexplored. Methods: To address this gap, we evaluated the protective effects of Api against D-gal-induced cognitive deficits through behavioral and histomorphological assessments. Untargeted metabolomics was performed to profile metabolic alterations in the locus coeruleus (LC), complemented by targeted metabolomics focusing on specific pathways. Putative targets were predicted by molecular docking and verified via cellular thermal shift assay (CETSA), while molecular biology approaches were adopted to elucidate the underlying signaling cascades. Results: Api significantly ameliorated D-gal-induced cognitive impairment and increased hippocampal NE and lactate levels with enhanced neuronal activity. Metabolomics indicated that Api regulates energy metabolism pathways including TCA cycle, amino acid metabolism, glycolysis/gluconeogenesis, and glutathione metabolism. Specifically, Api elevated NE and lactate in the LC. GPR30 was identified and validated as the key target via molecular docking and CETSA, showing strong binding affinity. Mechanistically, Api activates GPR30 on noradrenergic neurons to regulate PLCβ1-Ca ²⁺ -Syt1 signaling, promoting NE release, which in turn drives astrocytic glycogenolysis and lactate production, thereby relieving neuronal energy deficits. Conclusion: Collectively, this study not only clarifies the PLCβ1-Ca ²⁺ -Syt1-dependent mechanism of Api in aging-related cognitive impairment, but also highlights NE and lactate elevation as a promising therapeutic approach.
SN - 1663-9812
ER -