{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:23Z","timestamp":1787029103624,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T00:00:00Z","timestamp":1675036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Far Eastern Memorial Hospital","award":["FEMH-2022-C-001"],"award-info":[{"award-number":["FEMH-2022-C-001"]}]},{"name":"Far Eastern Memorial Hospital","award":["FEMH-2023-C-001"],"award-info":[{"award-number":["FEMH-2023-C-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Inhibiting the excessive release of glutamate in the brain is emerging as a promising therapeutic option and is efficient for treating neurodegenerative disorders. The aim of this study is to investigate the effect and mechanism of plantainoside D (PD), a phenylenthanoid glycoside isolated from Plantago asiatica L., on glutamate release in rat cerebral cortical nerve terminals (synaptosomes). We observed that PD inhibited the potassium channel blocker 4-aminopyridine (4-AP)-evoked release of glutamate and elevated concentration of cytosolic Ca2+. Using bafilomycin A1 to block glutamate uptake into synaptic vesicles and EDTA to chelate extracellular Ca2+, the inhibitory effect of PD on 4-AP-evoked glutamate release was prevented. In contrast, the action of PD on the 4-AP-evoked release of glutamate in the presence of dl-TBOA, a potent nontransportable inhibitor of glutamate transporters, was unaffected. PD does not alter the 4-AP-mediated depolarization of the synaptosomal membrane potential, suggesting that the inhibitory effect of PD on glutamate release is associated with voltage-dependent Ca2+ channels (VDCCs) but not the modulation of plasma membrane potential. Pretreatment with the Ca2+ channel blocker (N-type) \u03c9-conotoxin GVIA abolished the inhibitory effect of PD on the evoked glutamate release, as did pretreatment with the protein kinase C inhibitor GF109203x. However, the PD-mediated inhibition of glutamate release was eliminated by applying the mitochondrial Na+\/Ca2+ exchanger inhibitor CGP37157 or dantrolene, which inhibits Ca2+ release through ryanodine receptor channels. These data suggest that PD mediates the inhibition of evoked glutamate release from synaptosomes primarily by reducing the influx of Ca2+ through N-type Ca2+ channels, subsequently reducing the protein kinase C cascade.<\/jats:p>","DOI":"10.3390\/molecules28031313","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T04:31:27Z","timestamp":1675053087000},"page":"1313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Plantainoside D Reduces Depolarization-Evoked Glutamate Release from Rat Cerebral Cortical Synaptosomes"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7597-7655","authenticated-orcid":false,"given":"Kuan-Ming","family":"Chiu","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Surgery, Cardiovascular Center, Far-Eastern Memorial Hospital, New Taipei City 22060, Taiwan"},{"name":"Department of Electrical Engineering, Yuan Ze University, Taoyuan 32003, 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":"Department of Medical Research, Far-Eastern Memorial Hospital, New Taipei City 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\/0000-0002-1374-5189","authenticated-orcid":false,"given":"Tzu-Yu","family":"Lin","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\/0000-0002-4675-0259","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":[[2023,1,30]]},"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":"799","DOI":"10.1007\/s00702-014-1180-8","article-title":"Glutamate as a neurotransmitter in the healthy brain","volume":"121","author":"Zhou","year":"2014","journal-title":"J. Neural. Transm."},{"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":"379","DOI":"10.1038\/aps.2009.24","article-title":"Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases","volume":"30","author":"Dong","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40035-021-00278-7","article-title":"Excitotoxicity, calcium and mitochondria: A triad in synaptic neurodegeneration","volume":"11","author":"Verma","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_7","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_8","first-page":"356","article-title":"Screening of new chemopreventive compounds from Digitalis purpurea","volume":"61","author":"Lee","year":"2006","journal-title":"Pharmazie"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.3390\/molecules13092049","article-title":"New secoiridoid glycosides from the roots of Picrorhiza scrophulariiflora","volume":"13","author":"Zou","year":"2008","journal-title":"Molecules"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1002\/ptr.3071","article-title":"Bioguided isolation of angiotensin-converting enzyme inhibitors from the seeds of Plantago asiatica L.","volume":"24","author":"Geng","year":"2010","journal-title":"Phytother. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15103","DOI":"10.3390\/molecules190915103","article-title":"LC-ESI-MS\/MS analysis and pharmacokinetics of plantainoside D isolated from Chirita longgangensis var. hongyao, a potential anti-hypertensive active component in rats","volume":"19","author":"Wang","year":"2014","journal-title":"Molecules"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115800","DOI":"10.1016\/j.jep.2022.115800","article-title":"Effective materials and mechanisms study of Tibetan herbal medicine Lagotis integra W. W. Smith treating DSS-induced ulcerative colitis based on network pharmacology, molecular docking and experimental validation","volume":"301","author":"Wang","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1248\/cpb.52.615","article-title":"Antioxidative phenylethanoid and phenolic glycosides from Picrorhiza scrophulariiflora","volume":"52","author":"Wang","year":"2004","journal-title":"Chem. Pharm. Bull."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.lfs.2006.09.019","article-title":"Plantainoside D protects adriamycin-induced apoptosis in H9c2 cardiac muscle cells via the inhibition of ROS generation and NF-kappaB activation","volume":"80","author":"Kim","year":"2007","journal-title":"Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3389\/fphar.2019.00403","article-title":"Extract of Plantago asiatica L. seeds ameliorates hypertension in spontaneously hypertensive rats by inhibition of angiotensin converting enzyme","volume":"10","author":"Tong","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s10787-019-00680-8","article-title":"Therapeutic potential of IKK-\u03b2 inhibitors from natural phenolics for inflammation in cardiovascular diseases","volume":"28","author":"Zhou","year":"2020","journal-title":"Inflammopharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4739","DOI":"10.1039\/D2AN01185A","article-title":"A deep clustering-based mass spectral data visualization strategy for anti-renal fibrotic lead compound identification from natural products","volume":"147","author":"Lai","year":"2022","journal-title":"Analyst"},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"e21990","DOI":"10.1002\/syn.21990","article-title":"Alzheimer\u2019s disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration","volume":"71","author":"Espinosa","year":"2017","journal-title":"Synapse"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1021\/np9801460","article-title":"Isolation and structure elucidation of new PKC\u03b1 inhibitors from Pinus flexilis","volume":"61","author":"Lee","year":"1998","journal-title":"J. Nat. Prod."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1021\/np980147s","article-title":"Phenylethanoid glycosides from Digitalis purpurea and Penstemon linarioides with PKCalpha-inhibitory activity","volume":"61","author":"Zhou","year":"1998","journal-title":"J. Nat. Prod."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lu, C.W., Yeh, K.C., Chiu, K.M., Lee, M.Y., Lin, T.Y., and Wang, S.J. (2022). The effect of Isosaponarin derived from Wasabi leaves on glutamate release in rat synaptosomes and its underlying mechanism. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158752"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Magi, S., Piccirillo, S., Amoroso, S., and Lariccia, V. (2019). Excitatory amino acid transporters (EAATs): Glutamate transport and beyond. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225674"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Malik, A.R., and Willnow, T.E. (2019). Excitatory amino acid transporters in physiology and disorders of the central nervous system. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225671"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hung, Y.C., Kuo, Y.H., Hsieh, P.W., Hsieh, T.Y., Kuo, J.R., and Wang, S.J. (2021). Chlorogenic acid decreases glutamate release from rat cortical nerve terminals by P\/Q-type Ca2+ channel suppression: A possible neuroprotective mechanism. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111447"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eabi9027","DOI":"10.1126\/sciadv.abi9027","article-title":"Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals","volume":"7","author":"Pulido","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"113434","DOI":"10.1016\/j.expneurol.2020.113434","article-title":"Inhibition of sigma-1 receptors substantially modulates GABA and glutamate transport in presynaptic nerve terminals","volume":"333","author":"Pozdnyakova","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1007\/s10571-020-00980-6","article-title":"Histamine H3 receptor activation modulates glutamate release in the corticostriatal synapse by acting at CaV2.1 (P\/Q-Type) calcium channels and GIRK (KIR3) potassium channels","volume":"42","author":"Vega","year":"2022","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_29","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_30","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.cellsig.2015.12.014","article-title":"Differential role of SNAP-25 phosphorylation by protein kinases A and C in the regulation of SNARE complex formation and exocytosis in PC12 cells","volume":"28","author":"Gao","year":"2016","journal-title":"Cell. Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1523\/JNEUROSCI.4933-08.2010","article-title":"SNAP-25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking","volume":"30","author":"Lau","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Palanivel, V., Gupta, V., Mirshahvaladi, S.S.O., Sharma, S., Gupta, V., Chitranshi, N., Mirzaei, M., Graham, S.L., and Basavarajappa, D. (2022). Neuroprotective effects of neuropeptide Y on human neuroblastoma SH-SY5Y cells in glutamate excitotoxicity and ER stress conditions. Cells, 11.","DOI":"10.3390\/cells11223665"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pap, R., Pandur, E., J\u00e1nosa, G., Sipos, K., Nagy, T., Ag\u00f3cs, A., and Deli, J. (2022). Lutein decreases inflammation and oxidative stress and prevents iron accumulation and lipid peroxidation at glutamate-induced neurotoxicity. Antioxidants, 11.","DOI":"10.3390\/antiox11112269"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/0165-6147(90)90184-A","article-title":"Excitatory amino acid neurotoxicity and neurodegenerative disease","volume":"11","author":"Meldrum","year":"1990","journal-title":"Trends. Pharmacol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1111\/j.1460-9568.2007.05873.x","article-title":"Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca2+ signalling in hippocampal neurons","volume":"26","author":"Egea","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.neuint.2015.01.006","article-title":"The effects of JM-20 on the glutamatergic system in synaptic vesicles, synaptosomes and neural cells cultured from rat brain","volume":"81","author":"Ganzella","year":"2015","journal-title":"Neurochem. Int."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lu, C.W., Huang, Y.C., Chiu, K.M., Lee, M.Y., Lin, T.Y., and Wang, S.J. (2021). Enmein decreases synaptic glutamate release and protects against kainic acid-induced brain injury in rats. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312966"},{"key":"ref_38","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_39","doi-asserted-by":"crossref","unstructured":"Mahmoud, S., Gharagozloo, M., Simard, C., and Gris, D. (2019). Astrocytes maintain glutamate hmeostasis in the CNS by controlling the balance between glutamate uptake and release. Cells, 8.","DOI":"10.3390\/cells8020184"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"136123","DOI":"10.1016\/j.neulet.2021.136123","article-title":"Neurochemical abnormalities in the hippocampus of male rats displaying audiogenic seizures, a genetic model of epilepsy","volume":"761","author":"Bernardino","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_41","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_42","doi-asserted-by":"crossref","unstructured":"Lin, T.K., Hung, C.F., Weng, J.R., Hsieh, T.Y., and Wang, S.J. (2022). Kaempferol 3-Rhamnoside on glutamate release from rat cerebrocortical nerve terminals involves P\/Q-type Ca2+ channel and Ca2+\/calmodulin-dependent protein kinase II-dependent pathway suppression. Molecules, 27.","DOI":"10.3390\/molecules27041342"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0165-6147(00)01800-9","article-title":"Interactions between presynaptic Ca2+ channels, cytoplasmic messengers and proteins of the synaptic vesicle release complex","volume":"22","author":"Jarvis","year":"2001","journal-title":"Trends. Pharmacol. Sci."},{"key":"ref_44","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_45","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1002\/1096-9861(20001016)426:2<243::AID-CNE6>3.0.CO;2-8","article-title":"Distribution of protein kinase Mzeta and the complete protein kinase C isoform family in rat brain","volume":"426","author":"Naik","year":"2000","journal-title":"J. Comp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/joa.12106","article-title":"Protein kinase C isoforms at the neuromuscular junction: Localization and specific roles in neurotransmission and development","volume":"224","author":"Lanuza","year":"2014","journal-title":"J. Anat."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7996","DOI":"10.1038\/s41598-017-08237-x","article-title":"SNAP-25 phosphorylation at Ser187 regulates synaptic facilitation and short-term plasticity in an age-dependent manner","volume":"7","author":"Katayama","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1523\/JNEUROSCI.2352-07.2008","article-title":"Phosphorylation of SNAP-25 at Ser187 mediates enhancement of exocytosis by a phorbol ester in INS-1 cells","volume":"28","author":"Shu","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Lin, T.Y., Chen, I.Y., Lee, M.Y., Lu, C.W., Chiu, K.M., and Wang, S.J. (2022). Inhibition of glutamate release from rat cortical nerve terminals by dehydrocorydaline, an alkaloid from Corydalis yanhusuo. 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