{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:00:51Z","timestamp":1787313651826,"version":"build-2736575974"},"reference-count":47,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:00:00Z","timestamp":1643587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Far Eastern Memorial Hospital, Taiwan","award":["FEMH-2014-D-008"],"award-info":[{"award-number":["FEMH-2014-D-008"]}]},{"name":"Far Eastern Memorial Hospital, Taiwan","award":["FEMH-2015-C-056"],"award-info":[{"award-number":["FEMH-2015-C-056"]}]},{"name":"Far Eastern Memorial Hospital, Taiwan","award":["FEMH-2021-C-001"],"award-info":[{"award-number":["FEMH-2021-C-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Excessive release of glutamate induces excitotoxicity and causes neuronal damage in several neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for preventing and treating neurological disorders. Dehydrocorydaline (DHC), an active alkaloid compound isolated from Corydalis yanhusuo, possesses neuroprotective capacity. The present study investigated the effect of DHC on glutamate release using a rat brain cortical synaptosome model. Our results indicate that DHC inhibited 4-aminopyridine (4-AP)-evoked glutamate release and elevated intrasynaptosomal calcium levels. The inhibitory effect of DHC on 4-AP-evoked glutamate release was prevented in the presence of the vesicular transporter inhibitor bafilomycin A1 and the N- and P\/Q-type Ca2+ channel blocker \u03c9-conotoxin MVIIC but not the intracellular inhibitor of Ca2+ release dantrolene or the mitochondrial Na+\/Ca2+ exchanger inhibitor CGP37157. Moreover, the inhibitory effect of DHC on evoked glutamate release was prevented by the mitogen-activated protein kinase (MAPK)\/extracellular signal-regulated kinase (ERK) inhibitor PD98059. Western blotting data in synaptosomes also showed that DHC significantly decreased the level of ERK1\/2 phosphorylation and synaptic vesicle-associated protein synapsin I, the main presynaptic target of ERK. Together, these results suggest that DHC inhibits presynaptic glutamate release from cerebrocortical synaptosomes by suppressing presynaptic voltage-dependent Ca2+ entry and the MAPK\/ERK\/synapsin I signaling pathway.<\/jats:p>","DOI":"10.3390\/molecules27030960","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T08:20:29Z","timestamp":1643617229000},"page":"960","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Inhibition of Glutamate Release from Rat Cortical Nerve Terminals by Dehydrocorydaline, an Alkaloid from Corydalis yanhusuo"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1374-5189","authenticated-orcid":false,"given":"Tzu-Yu","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City 22060, Taiwan"},{"name":"Department of Mechanical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Yen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City 22060, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7742-9508","authenticated-orcid":false,"given":"Ming-Yi","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Surgery, Cardiovascular Center, Far-Eastern Memorial Hospital, New Taipei 22060, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2217-3231","authenticated-orcid":false,"given":"Cheng-Wei","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City 22060, Taiwan"},{"name":"Department of Mechanical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7597-7655","authenticated-orcid":false,"given":"Kuan-Ming","family":"Chiu","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Surgery, Cardiovascular Center, Far-Eastern Memorial Hospital, New Taipei 22060, Taiwan"},{"name":"Department of Nursing, Asia Eastern University of Science and Technology, New Taipei City 22060, Taiwan"},{"name":"Department of Photonics Engineering, Yuan Ze University, Taoyuan 32003, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4675-0259","authenticated-orcid":false,"given":"Su-Jane","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan"},{"name":"Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1007\/s11064-015-1622-1","article-title":"Glutamate Release","volume":"40","author":"Hackett","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0301-0082(00)00067-8","article-title":"Glutamate uptake","volume":"65","author":"Danbolt","year":"2001","journal-title":"Prog. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1007S","DOI":"10.1093\/jn\/130.4.1007S","article-title":"Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology","volume":"130","author":"Meldrum","year":"2000","journal-title":"J. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"469","DOI":"10.3389\/fnins.2015.00469","article-title":"Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence?","volume":"9","author":"Lewerenz","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s40263-015-0225-3","article-title":"Taming glutamate excitotoxicity: Strategic pathway modulation for neuroprotection","volume":"29","author":"Jia","year":"2015","journal-title":"CNS Drugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1139\/y76-042","article-title":"Adrenergic neuron blocking action of dehydrocorydaline isolated from Corydalis bulbosa","volume":"54","author":"Kurahashi","year":"1976","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1016\/j.intimp.2011.04.022","article-title":"Dehydrocorydaline inhibits elevated mitochondrial membrane potential in lipopolysaccharide-stimulated macrophages","volume":"11","author":"Ishiguro","year":"2011","journal-title":"Int. Immunopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1142\/S0192415X12500140","article-title":"Dehydrocorydaline inhibits breast cancer cells proliferation by inducing apoptosis in MCF-7 cells","volume":"40","author":"Xu","year":"2012","journal-title":"Am. J. Chin. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27129","DOI":"10.1038\/srep27129","article-title":"Antinociceptive effects of dehydrocorydaline in mouse models of inflammatory pain involve the opioid receptor and inflammatory cytokines","volume":"6","author":"Yin","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wen, B., Dang, Y.Y., Wu, S.H., Huang, Y.M., Ma, K.Y., Xu, Y.M., Zheng, X.L., and Dai, X.Y. (2021). Antiatherosclerotic effect of dehydrocorydaline on ApoE(-\/-) mice: Inhibition of macrophage inflammation. Acta Pharmacol. Sin.","DOI":"10.1038\/s41401-021-00769-3"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1211\/jpp.59.5.0010","article-title":"Beneficial effects of the extract from Corydalis yanhusuo in rats with heart failure following myocardial infarction","volume":"59","author":"Wu","year":"2007","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Guan, H., Li, K., Wang, X., Luo, X., Su, M., Tan, W., Chang, X., and Shi, Y. (2017). Identification of Metabolites of the Cardioprotective Alkaloid Dehydrocorydaline in Rat Plasma and Bile by Liquid Chromatography Coupled with Triple Quadrupole Linear Ion Trap Mass Spectrometry. Molecules, 22.","DOI":"10.3390\/molecules22101686"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"172725","DOI":"10.1016\/j.ejphar.2019.172725","article-title":"Dehydrocorydaline induced antidepressant-like effect in a chronic unpredictable mild stress mouse model via inhibiting uptake-2 monoamine transporters","volume":"864","author":"Jin","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1471-4159.1987.tb03393.x","article-title":"Calcium-dependent and -independent release of glutamate from synaptosomes monitored by continuous fluorometry","volume":"49","author":"Nicholls","year":"1987","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0079-6123(08)60427-6","article-title":"Presynaptic modulation of glutamate release","volume":"116","author":"Nicholls","year":"1998","journal-title":"Prog. Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/0304-3940(88)90742-2","article-title":"The effects of calcium channel agonists and antagonists on the release of endogenous glutamate from cerebellar slices","volume":"92","author":"Barnes","year":"1988","journal-title":"Neurosci. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/366156a0","article-title":"Different types of calcium channels mediate central synaptic transmission","volume":"366","author":"Takahashi","year":"1993","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0304-3940(02)00719-X","article-title":"Differential coupling of N- and P\/Q-type calcium channels to glutamate exocytosis in the rat cerebral cortex","volume":"330","year":"2002","journal-title":"Neurosci. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1111\/j.1460-9568.1997.tb01369.x","article-title":"Presynaptic modulation of glutamate release targets different calcium channels in rat cerebrocortical nerve terminals","volume":"9","year":"1997","journal-title":"Eur. J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2787","DOI":"10.1007\/s00018-013-1550-7","article-title":"Neuronal calcium signaling: Function and dysfunction","volume":"71","author":"Brini","year":"2014","journal-title":"Cell Mol. Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/j.neuropharm.2003.09.012","article-title":"Somatostatin inhibits glutamate release from mouse cerebrocortical nerve endings through presynaptic sst2 receptors linked to the adenylyl cyclase-protein kinase A pathway","volume":"46","author":"Grilli","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0028-3908(01)00162-9","article-title":"Non-specific effects of the MEK inhibitors PD098,059 and U0126 on glutamate release from hippocampal synaptosomes","volume":"42","author":"Pereira","year":"2002","journal-title":"Neuropharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1046\/j.1471-4159.2003.02065.x","article-title":"Co-activation of PKA and PKC in cerebrocortical nerve terminals synergistically facilitates glutamate release","volume":"87","author":"Torres","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/73888","article-title":"Synapsins as mediators of BDNF-enhanced neurotransmitter release","volume":"3","author":"Jovanovic","year":"2000","journal-title":"Nat. Neurosci."},{"key":"ref_25","first-page":"S7","article-title":"Anatomy and physiology of glutamate in the CNS","volume":"44","author":"Greenamyre","year":"1994","journal-title":"Neurology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/BF00966922","article-title":"Mechanisms in the regulation of neurotransmitter release from brain nerve terminals: Current hypotheses","volume":"18","author":"Sihra","year":"1993","journal-title":"Neurochem. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1111\/j.1471-4159.1989.tb09232.x","article-title":"Repetitive action potentials in isolated nerve terminals in the presence of 4-aminopyridine: Effects on cytosolic free Ca2+ and glutamate release","volume":"53","author":"Tibbs","year":"1989","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/0896-6273(93)90145-H","article-title":"Nonvesicular release of neurotransmitter","volume":"11","author":"Attwell","year":"1993","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1021\/acs.chemrestox.0c00446","article-title":"Typhaneoside Suppresses Glutamate Release Through Inhibition of Voltage-Dependent Calcium Entry in Rat Cerebrocortical Nerve Terminals","volume":"34","author":"Chiu","year":"2021","journal-title":"Chem. Res. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1073\/pnas.93.8.3679","article-title":"Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions","volume":"93","author":"Jovanovic","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0896-6273(03)00151-X","article-title":"Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies","volume":"38","author":"Chi","year":"2003","journal-title":"Neuron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s11068-007-9013-4","article-title":"Vesicle pools and synapsins: New insights into old enigmas","volume":"35","author":"Fdez","year":"2006","journal-title":"Brain Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11909","DOI":"10.1021\/jf302875k","article-title":"Coenzyme Q10 inhibits the release of glutamate in rat cerebrocortical nerve terminals by suppression of voltage-dependent calcium influx and mitogen-activated protein kinase signaling pathway","volume":"60","author":"Chang","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0169-328X(00)00231-X","article-title":"A novel function of synapsin II in neurotransmitter release","volume":"85","author":"Sugiyama","year":"2000","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.jpba.2013.12.037","article-title":"Simultaneous determination of four alkaloids in mice plasma and brain by LC-MS\/MS for pharmacokinetic studies after administration of Corydalis Rhizoma and Yuanhu Zhitong extracts","volume":"92","author":"Gao","year":"2014","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"951","DOI":"10.3390\/molecules17010951","article-title":"Effect of wine and vinegar processing of Rhizoma Corydalis on the tissue distribution of tetrahydropalmatine, protopine and dehydrocorydaline in rats","volume":"17","author":"Dou","year":"2012","journal-title":"Molecules"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"709604","DOI":"10.3389\/fphar.2021.709604","article-title":"Dehydrocorydaline Protects Against Sepsis-Induced Myocardial Injury Through Modulating the TRAF6\/NF-\u03baB Pathway","volume":"12","author":"Li","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.7901908","article-title":"Oxidative stress, glutamate, and neurodegenerative disorders","volume":"262","author":"Coyle","year":"1993","journal-title":"Science"},{"key":"ref_39","first-page":"401","article-title":"The oxidative stress hypothesis in Alzheimer\u2019s disease","volume":"25","author":"Padurariu","year":"2013","journal-title":"Psychiatr. Danub."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.neuropharm.2003.11.025","article-title":"Excessive and precocious glutamate release in a mouse model of amyotrophic lateral sclerosis","volume":"46","author":"Raiteri","year":"2004","journal-title":"Neuropharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/syn.1030","article-title":"Effects of lubeluzole on the methamphetamine-induced increase in extracellular glutamate and the long-term depletion of striatal dopamine","volume":"40","author":"Wallace","year":"2001","journal-title":"Synapse"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.neuroscience.2004.01.019","article-title":"Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes)","volume":"125","author":"Wang","year":"2004","journal-title":"Neuroscience"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sajeeda, S., Kumar, L., and Verma, R. (2021). Lamotrigine-A Review of Analytical Methods Developed for Pharmaceutical Formulations and Biological Matrices. Crit. Rev. Anal. Chem.","DOI":"10.1080\/10408347.2021.1886901"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4181696","DOI":"10.1155\/2020\/4181696","article-title":"Dehydrocorydaline Accounts the Majority of Anti-Inflammatory Property of Corydalis Rhizoma in Cultured Macrophage","volume":"2020","author":"Kong","year":"2020","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lu, C.W., Lin, T.Y., Chiu, K.M., Lee, M.Y., Huang, J.H., and Wang, S.J. (2020). Silymarin inhibits glutamate release and prevents against kainic acid-induced excitotoxic injury in rats. Biomedicines, 8.","DOI":"10.3390\/biomedicines8110486"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wang, C.-C., Hsieh, P.-W., Kuo, J.-R., and Wang, S.-J. (2021). Rosmarinic Acid, a Bioactive Phenolic Compound, Inhibits Glutamate Release from Rat Cerebrocortical Synaptosomes through GABAA Receptor Activation. Biomolecules, 11.","DOI":"10.3390\/biom11071029"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1016\/S0021-9258(19)83641-4","article-title":"A new generation of Ca2+ indicators with greatly improved fluorescence properties","volume":"260","author":"Grynkiewicz","year":"1985","journal-title":"J. Biol. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/3\/960\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:11:48Z","timestamp":1760134308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/3\/960"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,31]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["molecules27030960"],"URL":"https:\/\/doi.org\/10.3390\/molecules27030960","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,31]]}}}