{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:39Z","timestamp":1787028579327,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Israeli Ministry of Innovation, Science and Technology","award":["97231"],"award-info":[{"award-number":["97231"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oxidative-stress-induced neuronal injury is a major contributor to neurodegenerative diseases, underscoring the need for novel neuroprotective strategies. Natural products with antioxidant and mitochondrial-stabilizing properties are increasingly recognized as promising multi-target therapeutics. Ficus benjamina L., a member of the Moraceae family, is rich in flavonoids and traditionally used in Asian ethnomedicine for wound healing, inflammation, and weakness, with related Ficus species documented in the Bencao Gangmu (Compendium of Materia Medica) for circulation and detoxification disorders. However, its neuroprotective potential has not been systematically evaluated. In this study, we explored the neuroprotective potential of a flavonoid-enriched 80% methanolic leaf extract of F. benjamina by evaluating its capacity to mitigate oxidative stress in neuronal cells and a murine optic nerve crush (ONC) injury model. We observed in SH-SY5Y cells that cell viability was preserved after pre-treatment using the extract, mitochondrial respiration and the membrane potential were maintained, and gene expression was modulated by upregulation of BCL-2 (B-cell lymphoma 2), BCL-xL (B-cell lymphoma-extra large), X) SOD2 (Superoxide Dismutase), CAT (Catalase), and BDNF (Brain-Derived Neurotrophic Factor). Intravitreal delivery of the extract in vivo resulted in a marked increase in the survival of retinal ganglion cells following ONC injury. Caffeic acid, quercetin-3-O-rutinoside, and kaempferol-3-O-rutinoside were identified as major constituents in phytochemical profiling. These results indicate that F. benjamina exerts multi-target neuroprotective actions, mediated via mitochondrial regulation, enhancement of antioxidation defenses, and modulation of apoptotic pathways. The findings also substantiate the contemporary pharmacological relevance underscoring the ethnomedicinal use of Ficus species and highlight the potential of F. benjamina as a promising candidate for developing integrative therapeutic approaches to target neurodegenerative diseases driven by oxidative stress.<\/jats:p>","DOI":"10.3390\/ijms262311746","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T13:53:30Z","timestamp":1764856410000},"page":"11746","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Multi-Target Neuroprotective Effects of Flavonoid-Rich Ficus benjamina L. Leaf Extracts: Mitochondrial Modulation, Antioxidant Defense, and Retinal Ganglion Cell Survival In Vivo"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-3514","authenticated-orcid":false,"given":"Arik","family":"Dahan","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moria","family":"Oz","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4962-4938","authenticated-orcid":false,"given":"Ludmila","family":"Yarmolinsky","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9451-5253","authenticated-orcid":false,"given":"Alon","family":"Zahavi","sequence":"additional","affiliation":[{"name":"Ophthalmology Department and Eye Research Laboratory, Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 4941492, Israel"},{"name":"Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5648-1873","authenticated-orcid":false,"given":"Nitza","family":"Goldenberg-Cohen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Bnai-Zion Medical Center, Haifa 3339419, Israel"},{"name":"Krieger Eye Research Laboratory, Ruth and Bruce Faculty of Medicine, Technion\u2014Institute of Technology, Haifa 3200003, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1695-6544","authenticated-orcid":false,"given":"Boris","family":"Khalfin","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7551-5488","authenticated-orcid":false,"given":"Shimon","family":"Ben-Shabat","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bat Chen R.","family":"Lubin","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Biotechnology and Materials, Ariel University, Ariel 40700, Israel"},{"name":"Agriculture and Oenology Department, Eastern Regional R&D Center, Ariel 40700, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102758","DOI":"10.1016\/j.eclinm.2024.102758","article-title":"Global, Regional, and National Burden of Ischemic Stroke, 1990\u20132021: An Analysis of Data from the Global Burden of Disease Study 2021","volume":"75","author":"Li","year":"2024","journal-title":"EClinicalMedicine"},{"key":"ref_2","unstructured":"Laurent, D., Small, C.N., Goutnik, M., and Hoh, B. 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