{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T14:55:25Z","timestamp":1770821725128,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,8,6]],"date-time":"2022-08-06T00:00:00Z","timestamp":1659744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["110-2320-B-030-009"],"award-info":[{"award-number":["110-2320-B-030-009"]}]},{"name":"Ministry of Science and Technology","award":["110-2314-B-418-008"],"award-info":[{"award-number":["110-2314-B-418-008"]}]},{"name":"Ministry of Science and Technology","award":["TYAFGH-A-111017"],"award-info":[{"award-number":["TYAFGH-A-111017"]}]},{"name":"Taoyuan Armed Forces General Hospital","award":["110-2320-B-030-009"],"award-info":[{"award-number":["110-2320-B-030-009"]}]},{"name":"Taoyuan Armed Forces General Hospital","award":["110-2314-B-418-008"],"award-info":[{"award-number":["110-2314-B-418-008"]}]},{"name":"Taoyuan Armed Forces General Hospital","award":["TYAFGH-A-111017"],"award-info":[{"award-number":["TYAFGH-A-111017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Excessive glutamate release is known to be involved in the pathogenesis of neurological diseases, and suppression of glutamate release from nerve terminals is considered to be a treatment strategy. In this study, we investigated whether isosaponarin, a flavone glycoside isolated from wasabi leaves, could affect glutamate release in rat cerebral cortex nerve terminals (synaptosomes). The release of glutamate was evoked by the K+ channel blocker 4-aminopyridine (4-AP) and measured by an online enzyme-coupled fluorimetric assay. Isosaponarin produced a concentration-dependent inhibition of 4-AP-evoked glutamate release with a half-maximum inhibition of release value of 22 \u03bcM. The inhibition caused by isosaponarin was prevented by eliminating extracellular Ca2+ or by using bafilomycin A1, an inhibitor of synaptic vesicle exocytosis. Isosaponarin decreased intrasynaptosomal rises in Ca2+ levels that were induced by 4-AP, without affecting the synaptosomal membrane potential. The isosaponarin-induced inhibition of glutamate release was significantly prevented in synaptosomes that were pretreated with a combination of the calcium channel blockers \u03c9-conotoxin GVIA (N-type) and \u03c9-agatoxin IVA (P\/Q-types). The protein kinase C (PKC) pan-inhibitor GF109203X and the Ca2+-dependent PKC inhibitor Go6976 abolished the inhibition of glutamate release by isosaponarin, while the Ca2+-independent PKC inhibitor rottlerin did not show any effect. The results from immunoblotting assays also showed that isosaponarin lowered PKC, PKC\u03b1, synaptosomal-associated protein of 25 kDa (SNAP-25), and myristoylated alanine-rich C-kinase substrate (MARCKS) phosphorylation induced by 4-AP. In addition, FM1-43-labeled synaptic vesicles in synaptosomes showed that treatment with isosaponarin resulted in an attenuation of the 4-AP-induced decrease in fluorescence intensity that is consistent with glutamate release. Transmission electron microscopy of synaptosomes also provided evidence that isosaponarin altered the number of synaptic vesicles. These results indicate that isosaponarin suppresses the Ca2+-dependent PKC\/SNAP-25 and MARCKS pathways in synaptosomes, causing a decrease in the number of available synaptic vesicles, which inhibits vesicular glutamate release from synaptosomes.<\/jats:p>","DOI":"10.3390\/ijms23158752","type":"journal-article","created":{"date-parts":[[2022,8,7]],"date-time":"2022-08-07T22:51:46Z","timestamp":1659912706000},"page":"8752","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The Effect of Isosaponarin Derived from Wasabi Leaves on Glutamate Release in Rat Synaptosomes and Its Underlying Mechanism"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2217-3231","authenticated-orcid":false,"given":"Cheng-Wei","family":"Lu","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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun-Chieh","family":"Yeh","sequence":"additional","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan"},{"name":"Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan 325208, Taiwan"},{"name":"Department of Surgery, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City 24205, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 City 22060, Taiwan"},{"name":"Department of Electrical Engineering, Yuan Ze University, Taoyuan 32003, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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 22060, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]},{"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":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/0896-6273(88)90162-6","article-title":"Glutamate neurotoxicity and diseases of the nervous system","volume":"1","author":"Choi","year":"1988","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3338","DOI":"10.1096\/fasebj.6.15.1464368","article-title":"Mechanisms of excitotoxicity in neurologic diseases","volume":"6","author":"Beal","year":"1992","journal-title":"FASEB J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.neuropharm.2018.09.021","article-title":"Riluzole attenuates the efficacy of glutamatergic transmission by interfering with the size of the readily releasable neurotransmitter pool","volume":"143","author":"Lazarevic","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lazarevic, V., Mantas, I., Flais, I., and Svenningsson, P. 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