{"doi":"10.1111/cns.14724","title":"Quercetin alleviates chronic unpredictable mild stress‐induced depression‐like behavior by inhibiting NMDAR1 with α2δ‐1 in rats","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Chronic unpredictable mild stress (CUMS) can lead to a significant acceleration of depression development. Quercetin (Que) is a flavonoid compound with a wide range of pharmacological effects. Recent studies have shown that quercetin can improve CUMS‐induced depression‐like behavior, but the mechanism of its improvement is still unclear. α2δ‐1 is a regulatory subunit of voltage‐gated calcium channel, which can interact with N‐methyl‐D‐aspartate receptor (NMDAR) to form a complex.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>In this study, we found that Que could inhibit the increase of α2δ‐1 and NMDAR expression in rat hypothalamus induced by CUMS. In pain, chronic hypertension and other studies have shown that α2δ‐1 interacts with the NMDAR to form a complex, which subsequently affects the expression level of NMDAR. Consequently, the present study aimed to investigate the antidepressant effect of Que in vivo and in vitro and to explore its mechanism of action in terms of the interaction between α2δ‐1 and NMDAR.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Rats were randomly exposed to two stressors every day for 4 weeks to establish a CUMS rat model, then sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT) were performed to detect the behavior of CUMS rats, so as to evaluate whether the CUMS rat model was successfully established and the improvement effect of Que on CUMS‐induced depression‐like behavior in rats. Experimental techniques such as serum enzyme‐linked immunosorbent assay (ELISA), immunofluorescence, Western blot, and co‐immunoprecipitation, as well as in vitro experiments, were used to investigate the mechanisms by which Que exerts its antidepressant effects.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Behavioral and ELISA test results showed that Que could produce a reduction in the excitability of the hypothalamic–pituitary–adrenal (HPA) axis in CUMS rats and lead to significant improvements in their depressive behavior. Western blot, immunofluorescence, and co‐immunoprecipitation experiments showed that Que produced a decrease in NMDAR1 and α2δ‐1 expression levels and interfered with α2δ‐1 and NMDAR1 binding. In addition, the neural regulation mechanism of Que on antidepressant effect in PC12 cells knocked out α2δ‐1 gene was further verified. Cellular experiments demonstrated that Que led to a reversal of up‐regulation of NMDAR1 and α2δ‐1 expression levels in corticosterone‐injured PC12 cells, while Que had no effects on NMDAR1 expression in PC12 cells with the α2δ‐1 gene knockout.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Que has a good antidepressant effect and can significantly improve the depression‐like behavior caused by CUMS. It exerts antidepressant effects by inhibiting the expression level of α2δ‐1, interfering with the interaction between α2δ‐1 and NMDAR, and then reducing the excitability of the HPA axis.</jats:p></jats:sec>","journal":"CNS Neuroscience &amp; Therapeutics","year":2024,"id":620938,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":589698,"name":"Xin Wei","orcid":"0000-0002-4761-5649","position":1,"is_corresponding":false},{"id":1603111,"name":"Yugai Jia","orcid":null,"position":2,"is_corresponding":false},{"id":1603112,"name":"Chaonan Wang","orcid":null,"position":3,"is_corresponding":false},{"id":1603113,"name":"Xinliu Wang","orcid":null,"position":4,"is_corresponding":false},{"id":237871,"name":"Xin Zhang","orcid":"0000-0001-9751-7054","position":5,"is_corresponding":false},{"id":1603114,"name":"Depei Li","orcid":null,"position":6,"is_corresponding":false},{"id":1109275,"name":"Yuanyuan Wang","orcid":"0000-0002-5576-6375","position":7,"is_corresponding":false},{"id":1603115,"name":"Yonggang Gao","orcid":"0000-0001-6865-4260","position":8,"is_corresponding":false},{"id":1603110,"name":"Mingyan Wang","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Quercetin alleviates chronic unpredictable mild stress‐induced depression‐like behavior by inhibiting NMDAR1 with α2δ‐1 in rats","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Chronic unpredictable mild stress (CUMS) can lead to a significant acceleration of depression development. Quercetin (Que) is a flavonoid compound with a wide range of pharmacological effects. Recent studies have shown that quercetin can improve CUMS‐induced depression‐like behavior, but the mechanism of its improvement is still unclear. α2δ‐1 is a regulatory subunit of voltage‐gated calcium channel, which can interact with N‐methyl‐D‐aspartate receptor (NMDAR) to form a complex.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>In this study, we found that Que could inhibit the increase of α2δ‐1 and NMDAR expression in rat hypothalamus induced by CUMS. In pain, chronic hypertension and other studies have shown that α2δ‐1 interacts with the NMDAR to form a complex, which subsequently affects the expression level of NMDAR. Consequently, the present study aimed to investigate the antidepressant effect of Que in vivo and in vitro and to explore its mechanism of action in terms of the interaction between α2δ‐1 and NMDAR.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Rats were randomly exposed to two stressors every day for 4 weeks to establish a CUMS rat model, then sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT) were performed to detect the behavior of CUMS rats, so as to evaluate whether the CUMS rat model was successfully established and the improvement effect of Que on CUMS‐induced depression‐like behavior in rats. Experimental techniques such as serum enzyme‐linked immunosorbent assay (ELISA), immunofluorescence, Western blot, and co‐immunoprecipitation, as well as in vitro experiments, were used to investigate the mechanisms by which Que exerts its antidepressant effects.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Behavioral and ELISA test results showed that Que could produce a reduction in the excitability of the hypothalamic–pituitary–adrenal (HPA) axis in CUMS rats and lead to significant improvements in their depressive behavior. Western blot, immunofluorescence, and co‐immunoprecipitation experiments showed that Que produced a decrease in NMDAR1 and α2δ‐1 expression levels and interfered with α2δ‐1 and NMDAR1 binding. In addition, the neural regulation mechanism of Que on antidepressant effect in PC12 cells knocked out α2δ‐1 gene was further verified. Cellular experiments demonstrated that Que led to a reversal of up‐regulation of NMDAR1 and α2δ‐1 expression levels in corticosterone‐injured PC12 cells, while Que had no effects on NMDAR1 expression in PC12 cells with the α2δ‐1 gene knockout.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Que has a good antidepressant effect and can significantly improve the depression‐like behavior caused by CUMS. It exerts antidepressant effects by inhibiting the expression level of α2δ‐1, interfering with the interaction between α2δ‐1 and NMDAR, and then reducing the excitability of the HPA axis.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":3.295836866004329,"endowment":3.295836866004329,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38615365","pmcid":"PMC11016343","openalex_id":"https://openalex.org/W4394792870","authors":[],"funders":[{"funder_name":"Ministry of Education's 'Chunhui Plan' Cooperative Research Project","grant_id":"202200159","title":null},{"funder_name":"Traditional Chinese Medicine of the Natural Science Foundation of Hebei Province","grant_id":"H2022423381","title":null},{"funder_name":"Research Foundation of Education Department of Hebei Province","grant_id":"QN2022006","title":null},{"funder_name":"Central Guiding Local Science and Technology Development Fund Projects","grant_id":"236Z7702G","title":null},{"funder_name":"Doctoral research Fund project of Hebei University of Traditional Chinese Medicine","grant_id":"BSZ2019011","title":null},{"funder_name":"Special fund for basic scientific research expenses of provincial colleges and universities of Hebei University of Traditional Chinese Medicine","grant_id":"YXTD2023003","title":null},{"funder_name":"Natural Science Fund Project of Hebei Province","grant_id":"H2020423004","title":null},{"funder_name":"Excellent Young Teacher Fundamental Research of Hebei University of Chinese Medicine","grant_id":"YQ2020009","title":null}],"total_grants":8,"fwci":4.9673,"citation_percentile":0.96316651,"influential_citations":0,"citation_trend":[{"year":2024,"count":3},{"year":2025,"count":13},{"year":2026,"count":10}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cns.14724","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cns.14724","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.14724","host_type":"publisher"},{"url":"https://doi.org/10.1111/cns.14724","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38615365","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11016343","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11016343/pdf/CNS-30-e14724.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11016343","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11016343?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Neurotransmitter Receptor Influence on Behavior","Stress Responses and Cortisol","Treatment of Major Depression","Humans","Animals","Rats","Receptors, N-Methyl-D-Aspartate","Quercetin","Depression","Hypothalamo-Hypophyseal System","Pituitary-Adrenal System","Antidepressive Agents"],"mesh_terms":["Animals","Antidepressive Agents","Depression","Humans","Hypothalamo-Hypophyseal System","Pituitary-Adrenal System","Quercetin","Receptors, N-Methyl-D-Aspartate","Rats"],"keywords":["Behavioural despair test","Open field","Quercetin","NMDA receptor","Tail suspension test","Stressor","Antidepressant","In vivo","Pharmacology","Hippocampus","Mechanism (biology)","Medicine","Depression (economics)","Chronic stress","Internal medicine","Chemistry","Neuroscience","Endocrinology","Psychology","Receptor","Biology","Biochemistry","Depression","NMDAR1","Hpa Axis","Cums","Α2δ‐1"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T12:38:43.028666Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}