{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:08:34Z","timestamp":1790053714793,"version":"4.0.1"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Science, Innovation and Universities and the State Research Agency","award":["PID2021-128133NB-I00"],"award-info":[{"award-number":["PID2021-128133NB-I00"]}],"id":[{"id":"https:\/\/ror.org\/05r0vyz12","id-type":"ROR","asserted-by":"crossref"}]},{"award":["PID2021-128133NB-I00"],"award-info":[{"award-number":["PID2021-128133NB-I00"]}],"id":[{"id":"https:\/\/ror.org\/05r0vyz12","id-type":"ROR","asserted-by":"publisher"}]},{"name":"European Regional Development Fund"},{"id":[{"id":"https:\/\/ror.org\/01rkhv978","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Spanish Ministry of Science and Innovation and the State Research Agency","award":["PID2019-110183RB-C22"],"award-info":[{"award-number":["PID2019-110183RB-C22"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Origanum majorana L. has reported antioxidant and other bioactive properties, but its effects on excitability and intracellular Ca2+ handling in excitable cells remain poorly defined. We investigated how a hydroalcoholic marjoram extract modulates membrane ion currents, cytosolic Ca2+ signaling, and MTT-reducing activity in bovine chromaffin cells and primary rat cortical neurons. Methods: A pressurized liquid O. majorana extract (ethanol:water, 70:30) was chemically characterized by HPLC-PAD. Whole-cell patch-clamp and current-clamp recordings were used to assess voltage-dependent Ca2+, Na+, and K+ currents and membrane excitability in bovine chromaffin cells. Fluo-4-AM measurements were used to evaluate Ca2+ responses to K+, caffeine, and histamine. MTT assays assessed changes in MTT-reducing activity under veratridine-induced Ca2+ overload and oligomycin\/rotenone-induced mitochondrial stress in bovine chromaffin cells and cortical neurons prepared from embryonic day 18 Sprague-Dawley rats. For inferential statistics, replicate cells or wells from the same primary culture were averaged and the independent culture was used as the biological unit. Results: Culture-level analysis confirmed significant reductions in voltage-dependent Ca2+ and Na+ currents at 1.5 \u00b5g\/mL (1 \u00b5L\/mL) marjoram extract, together with significant overall effects on the putative Ca2+-dependent and voltage-dependent K+ current components. The extract depolarized the resting membrane potential and markedly suppressed repetitive action-potential firing. Mean K+-evoked Fluo-4 responses were reduced by approximately 20%, although this effect did not reach statistical significance at the culture level. Caffeine-evoked Ca2+ responses were higher in the presence of 0.015\u20131.5 \u00b5g\/mL (0.01\u20131 \u00b5L\/mL) marjoram extract, but these differences did not remain significant after correction for multiple comparisons. Histamine-evoked responses were unchanged. In MTT assays, significant preservation of MTT-reducing activity was limited to selected conditions, mainly at lower extract concentrations in bovine chromaffin cells, whereas the neuronal comparisons did not remain significant after multiplicity correction. Because extract-only, concentration-matched vehicle, cell-free extract\/MTT interference controls, and an independent orthogonal assay of cell number or membrane integrity were not included, the MTT findings are reported strictly as changes in MTT-reducing activity and not as direct evidence of cytoprotection or neuroprotection. Conclusions:O. majorana extract modulates membrane excitability through effects on multiple plasma-membrane ion currents. The higher mean caffeine-evoked Ca2+ responses are compatible with altered Ca2+ mobilization from ryanodine-sensitive intracellular stores, but they do not demonstrate direct activation or sensitization of RyR receptors. The MTT findings do not establish cytoprotection or neuroprotection. These findings are correlative, and a causal contribution of ryanodine-sensitive intracellular stores to the preservation of MTT-reducing cellular metabolic activity remains to be established.<\/jats:p>","DOI":"10.3390\/ph19091493","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1493","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Marjoram Extract Modulates Ion Currents, Intracellular Calcium Signaling, and MTT-Reducing Activity in Bovine Chromaffin Cells and Rat Cortical Neurons"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6628-6097","authenticated-orcid":false,"given":"Ricardo","family":"de Pascual","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Mar\u00eda Arribas","family":"Tejedor","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Amor","sequence":"additional","affiliation":[{"name":"Department of Physiology, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, C\/Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2556-1835","authenticated-orcid":false,"given":"Laura","family":"Jaime","sequence":"additional","affiliation":[{"name":"Department of Production and Characterization of Novel Foods, Food Science Research Institute (CIAL) (UAM + CSIC), Universidad Aut\u00f3noma de Madrid, C\/Nicol\u00e1s Cabrera 9, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2366-7268","authenticated-orcid":false,"given":"Marisol","family":"Villalva","sequence":"additional","affiliation":[{"name":"Department of Production and Characterization of Novel Foods, Food Science Research Institute (CIAL) (UAM + CSIC), Universidad Aut\u00f3noma de Madrid, C\/Nicol\u00e1s Cabrera 9, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9976-0717","authenticated-orcid":false,"given":"Susana","family":"Santoyo","sequence":"additional","affiliation":[{"name":"Department of Production and Characterization of Novel Foods, Food Science Research Institute (CIAL) (UAM + CSIC), Universidad Aut\u00f3noma de Madrid, C\/Nicol\u00e1s Cabrera 9, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Victoria Jimenez","family":"Carretero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1336-303X","authenticated-orcid":false,"given":"Minerva Reyes","family":"Almodovar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier Hern\u00e1ndez","family":"Campano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9178-8822","authenticated-orcid":false,"given":"Miriam","family":"Granado","sequence":"additional","affiliation":[{"name":"Department of Physiology, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, C\/Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7011-5351","authenticated-orcid":false,"given":"Jes\u00fas M.","family":"Hern\u00e1ndez-Guijo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"},{"name":"Ram\u00f3n y Cajal Institute for Health Research, IRYCIS, Hospital Ram\u00f3n y Cajal, Ctra. de Colmenar Viejo, Km. 9100, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113318","DOI":"10.1016\/j.jep.2020.113318","article-title":"Traditional use, phytochemistry, toxicology, and pharmacology of Origanum majorana L.","volume":"265","author":"Bouyahya","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kakouri, E., Daferera, D., Kanakis, C., Revelou, P.K., Kaparakou, E.H., Dervisoglou, S., Perdikis, D., and Tarantilis, P.A. (2022). Origanum majorana essential oil\u2014A review of its chemical profile and pesticide activity. 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