{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:00:31Z","timestamp":1785405631822,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007414","name":"Qassim University","doi-asserted-by":"crossref","award":["QU-APC-2026"],"award-info":[{"award-number":["QU-APC-2026"]}],"id":[{"id":"10.13039\/501100007414","id-type":"DOI","asserted-by":"crossref"}]},{"award":["QU-APC-2026"],"award-info":[{"award-number":["QU-APC-2026"]}],"id":[{"id":"https:\/\/ror.org\/01wsfe280","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Monosodium glutamate (E621) is a common flavor enhancer in highly processed food. Although it makes food more enjoyable, chronic intake may lead to excitotoxicity in brain areas. The current study investigates histological and biochemical neurodegenerative alterations in the rat hippocampus following E621 administration and evaluates the potential neuroprotective properties of ascorbic acid (AA) against E621-induced adverse effects. Forty adult male albino rats were divided into four groups: control group (G1), AA group (G2), E621 group (G3), and AA + E621 group (G4). All animals received a daily intraperitoneal (IP) injection for 30 days. Hippocampal samples were processed and stained with hematoxylin and eosin (H&amp;E), immunostained for GFAP, synaptophysin (a synaptic protein), and caspase-3, and biochemically analyzed for oxidative markers, including malondialdehyde (MDA) and superoxide dismutase (SOD). G3 exhibited significant neurodegenerative changes, characterized by pyknotic granular cells and cytoplasmic vacuolation, with significantly elevated GFAP, synaptophysin, and caspase-3 immunoreactivity in the dentate gyrus (DG). These structural deficits correlated with elevated MDA levels and reduced SOD levels in G3. In contrast, simultaneous administration of AA with E621 resulted in substantial preservation of neuronal morphology, a reduction in caspase-3 immunoreactivity, and a restoration of synaptic vesicle density in G4. E621 induces hippocampal injury by increasing ROS levels and dysregulating GFAP, synaptophysin, and caspase-3. At the same time, AA preserves neuronal integrity and synaptic homeostasis, suggesting its potential role as a protective dietary supplement against brain injury induced by the E621 flavor enhancer.<\/jats:p>","DOI":"10.3390\/life16081234","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:26:23Z","timestamp":1785115583000},"page":"1234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ascorbic Acid Neuroprotection Against Hippocampal Injury and Gliosis Induced by E621 in Albino Rats Through Modulation of GFAP, Synaptophysin, and Caspase-3"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5427-7126","authenticated-orcid":false,"given":"Enas N.","family":"Morgan","sequence":"first","affiliation":[{"name":"Department of Physiotherapy, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5541-7928","authenticated-orcid":false,"given":"Ayman M.","family":"Mousa","sequence":"additional","affiliation":[{"name":"Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia"},{"name":"Department of Histology and Cell Biology, Benha Faculty of Medicine, Benha University, Benha 13518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4684-0414","authenticated-orcid":false,"given":"Rasha A.","family":"Elmansy","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanan","family":"Seleem","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"},{"name":"Department of Histology and Cell Biology, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0942-0285","authenticated-orcid":false,"given":"Marwa M.","family":"Fawzi","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Al Rayan National College of Medicine, Madinah 42541, Saudi Arabia"},{"name":"Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany Refaat","family":"Mahmoud","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"},{"name":"Department of Anatomy and Embryology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reham Abdulla","family":"Aboukhalil","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagir H. T.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7924-972X","authenticated-orcid":false,"given":"Reem A.","family":"Younis","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3920-6474","authenticated-orcid":false,"given":"Tarek Hamdy","family":"Abd-ElHamid","sequence":"additional","affiliation":[{"name":"Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt"},{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Aqaba Medical Sciences University, Aqaba 77110, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa","family":"Jabeen","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-7525","authenticated-orcid":false,"given":"Ashwag","family":"Alsharidah","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samah M.","family":"Abozaid","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Embryology, Faculty of Medicine, Minia University, Minia 61519, Egypt"},{"name":"Department of Basic Medical Sciences, Faculty of Medicine, Deraya University, New Minia 61768, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9306-609X","authenticated-orcid":false,"given":"Abdullah M.","family":"Alnuqaydan","sequence":"additional","affiliation":[{"name":"Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1962-9418","authenticated-orcid":false,"given":"Khaled E. A.","family":"Soliman","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8786-250X","authenticated-orcid":false,"given":"Enas Haridy","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Histology and Cell Biology, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt"},{"name":"Department of Anatomy, College of Medicine, Hail University, Ha\u2019il 55223, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"ckae144.234","DOI":"10.1093\/eurpub\/ckae144.234","article-title":"Food additive monosodium glutamate and risk of cardiovascular diseases: NutriNet-Sant\u00e9 cohort","volume":"34","author":"Javaux","year":"2024","journal-title":"Eur. J. Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1097\/j.pain.0000000000002592","article-title":"Systemic administration of monosodium glutamate induces sexually dimorphic headache- and nausea-like behaviours in rats","volume":"163","author":"Benbow","year":"2022","journal-title":"Pain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"106622","DOI":"10.1016\/j.microc.2021.106622","article-title":"Green spectrophotometric methods for the determination of monosodium glutamate in different matrices","volume":"169","author":"Ali","year":"2021","journal-title":"Microchem. J."},{"key":"ref_4","first-page":"1","article-title":"A mini review about monosodium glutamate","volume":"77","author":"Socaci","year":"2020","journal-title":"Bull. UASVM Food Sci. Technol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yoshida, R., and Ninomiya, Y. (2023). Umami and MSG. Umami: Taste for Health, Springer.","DOI":"10.1007\/978-3-031-32692-9_2"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.toxrep.2022.01.014","article-title":"The protective effect of Nigella sativa seeds against monosodium glutamate-induced hepatic dysfunction in rats","volume":"9","author":"Soliman","year":"2022","journal-title":"Toxicol. Rep."},{"key":"ref_7","first-page":"76","article-title":"Impact of monosodium glutamate on the liver of chick embryo: Histology, biochemical properties, and AVBD9 gene expression","volume":"13","author":"Islam","year":"2024","journal-title":"Int. J. Agric. Biosci."},{"key":"ref_8","first-page":"273","article-title":"Extensive use of monosodium glutamate: A threat to public health?","volume":"17","author":"Niaz","year":"2018","journal-title":"EXCLI J."},{"key":"ref_9","first-page":"416","article-title":"Natural products as safeguards against monosodium glutamate-induced toxicity","volume":"23","author":"Hajihasani","year":"2020","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1177\/0269881114563634","article-title":"Glutamate and dopamine in schizophrenia: An update for the 21st century","volume":"29","author":"Howes","year":"2015","journal-title":"J. Psychopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3960","DOI":"10.37506\/ijfmt.v15i3.15915","article-title":"Effects of monosodium glutamate (MSG) on neuron damages in hippocampus in Sprague-Dawley rats","volume":"15","author":"Razali","year":"2021","journal-title":"Indian J. Forensic Med. Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s12291-022-01077-1","article-title":"Monosodium glutamate even at low dose may affect oxidative stress, inflammation and neurodegeneration in rats","volume":"39","author":"Kesherwani","year":"2024","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Mudgal, R., Sharma, S., Singh, S., and Ravichandiran, V. (2023). The neuroprotective effect of ascorbic acid against imidacloprid-induced neurotoxicity and the role of HO-1 in mice. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1130575"},{"key":"ref_14","first-page":"81","article-title":"Comparative study between the neuroprotective effect of curcumin and vitamin C against neurotoxicity induced by acetamiprid on the cerebellum of male adult albino rats: A histological study","volume":"7","author":"Mohamed","year":"2024","journal-title":"SVU-Int. J. Med. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.32739\/jnbs.13.1.282","article-title":"Neuroprotective effect of Adansonia digitata fruit pulp extract against aluminum chloride-induced memory deficits and hippocampal damage in rats","volume":"13","author":"Suleiman","year":"2026","journal-title":"J. Neurobehav. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"107490","DOI":"10.1016\/j.nlm.2021.107490","article-title":"Amygdala-hippocampal interactions in synaptic plasticity and memory formation","volume":"184","author":"Roesler","year":"2021","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"229","DOI":"10.21608\/ejh.2018.4314.1013","article-title":"Efficacy of cerebrolysin on dentate gyrus of hippocampus after experimentally induced acute ischemic stroke in adult albino rats (histological, immunohistochemical, and biochemical study)","volume":"42","author":"Ahmed","year":"2019","journal-title":"Egypt. J. Histol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Schr\u00f6der, H., Moser, N., and Huggenberger, S. (2020). The mouse hippocampus. Neuroanatomy of the Mouse: An Introduction, Springer.","DOI":"10.1007\/978-3-030-19898-5"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/ahe.12496","article-title":"Adult neurogenesis in the mammalian dentate gyrus","volume":"49","author":"Abbott","year":"2020","journal-title":"Anat. Histol. Embryol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1007\/s00217-025-04723-z","article-title":"Histopathological and biochemical evaluation of the effects of monosodium glutamate on cognitive memory and brain functions in rats","volume":"251","author":"Erkartal","year":"2025","journal-title":"Eur. Food Res. Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1111\/1541-4337.12448","article-title":"A review of the alleged health hazards of monosodium glutamate","volume":"18","author":"Zanfirescu","year":"2019","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_22","first-page":"1","article-title":"Monosodium glutamate toxic effect on spleen structure and potentiality of recovery in adult albino rats","volume":"4","author":"Ebaid","year":"2012","journal-title":"Egypt. Acad. J. Biol. Sci. B Zool."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/S0076-6879(78)52032-6","article-title":"Microsomal lipid peroxidation","volume":"30","author":"Buege","year":"1978","journal-title":"Methods Enzymol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"110","DOI":"10.4103\/jasi.jasi_172_24","article-title":"The protective effect of melatonin against monosodium glutamate-induced hippocampal injury: Focus on regulating the Nrf2\/heme oxygenase-1 and nuclear factor-kappa B\/tumor necrosis factor-\u03b1\/caspase-3 and brain-derived neurotrophic factor signaling pathways in a rat model","volume":"74","author":"Amer","year":"2025","journal-title":"J. Anat. Soc. India"},{"key":"ref_25","first-page":"588","article-title":"Antioxidant-rich nutraceuticals as a therapeutic strategy for sickle cell disease","volume":"42","author":"Ibrahim","year":"2023","journal-title":"J. Am. Nutr. Assoc."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Buccellato, F.R., D\u2019Anca, M., Fenoglio, C., Scarpini, E., and Galimberti, D. (2021). Role of oxidative damage in Alzheimer\u2019s disease and neurodegeneration: From pathogenic mechanisms to biomarker discovery. Antioxidants, 10.","DOI":"10.3390\/antiox10091353"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jmau.2015.10.001","article-title":"Histological study on the protective role of ascorbic acid on cadmium-induced cerebral cortical neurotoxicity in adult male albino rats","volume":"4","author":"Afifi","year":"2016","journal-title":"J. Microsc. Ultrastruct."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.it.2020.07.004","article-title":"Astrocyte reactivity: Subtypes, states, and functions in CNS innate immunity","volume":"41","author":"Sofroniew","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Vishnumukkala, T., Che Mohd Nassir, C.M.N., Hein, Z.M., Kalerammana Gopalakrishna, P., Karikalan, B., Alkatiri, A., Jagadeesan, S., Naik, V.R., Thomas, W., and Mohd Moklas, M.A. (2025). Glial cells as emerging therapeutic targets in neurodegenerative diseases: Mechanistic insights and translational perspectives. Cells, 14.","DOI":"10.3390\/cells14191497"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1038\/s41401-025-01576-w","article-title":"Molecular mechanisms of excitotoxicity and their relevance to the pathogenesis of neurodegenerative diseases\u2014An update","volume":"46","author":"Wu","year":"2025","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9011","DOI":"10.1111\/jcmm.16864","article-title":"Excitotoxic stimulation activates distinct pathogenic and protective expression signatures in the hippocampus","volume":"25","author":"Caba","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_32","first-page":"410","article-title":"Effect of L-ascorbic acid and alpha-tocopherol on the monosodium glutamate-induced neurobehavioral changes in rats","volume":"41","author":"Saleh","year":"2021","journal-title":"Bull. Egypt. Soc. Physiol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Zhang, Y., and Bhavnani, B.R. (2005). Glutamate-induced apoptosis in primary cortical neurons is inhibited by equine estrogens via down-regulation of caspase-3 and prevention of mitochondrial cytochrome c release. BMC Neurosci., 6.","DOI":"10.1186\/1471-2202-6-13"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"24143","DOI":"10.1007\/s11356-022-23954-1","article-title":"Monosodium glutamate induces cortical oxidative, apoptotic, and inflammatory challenges in rats: The potential neuroprotective role of apigenin","volume":"30","author":"Albrakati","year":"2022","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s12031-016-0817-5","article-title":"Dual role of vitamin C on the neuroinflammation mediated neurodegeneration and memory impairments in colchicine-induced rat model of Alzheimer disease","volume":"60","author":"Sil","year":"2016","journal-title":"J. Mol. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.freeradbiomed.2008.12.018","article-title":"Vitamin C function in the brain: Vital role of the ascorbate transporter SVCT2","volume":"46","author":"Harrison","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/0301-0082(94)90052-3","article-title":"A vitamin as neuromodulator: Ascorbate release into the extracellular fluid of the striatum regulates dopaminergic transmission","volume":"43","author":"Rebec","year":"1994","journal-title":"Prog. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Nam, S.M., Seo, M., Seo, J.S., Rhim, H., Nahm, S.S., Cho, I.H., Chang, B.J., Kim, H.J., Choi, S.H., and Nah, S.Y. (2019). Ascorbic acid mitigates D-galactose-induced brain aging by increasing hippocampal neurogenesis and improving memory function. Nutrients, 11.","DOI":"10.3390\/nu11010176"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/8\/1234\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:11:54Z","timestamp":1785211914000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/8\/1234"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,26]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["life16081234"],"URL":"https:\/\/doi.org\/10.3390\/life16081234","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,26]]}}}