{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:31:41Z","timestamp":1785407501687,"version":"3.56.0"},"reference-count":54,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University","award":["KFU260924"],"award-info":[{"award-number":["KFU260924"]}]},{"award":["KFU260924"],"award-info":[{"award-number":["KFU260924"]}],"id":[{"id":"https:\/\/ror.org\/00dn43547","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Excitotoxicity caused by excessive activation of glutamate receptors, particularly N-methyl-D-aspartate receptors (NMDARs), significantly contributes to neuronal damage in neurodegenerative diseases (NDDs), such as Alzheimer\u2019s, Parkinson\u2019s, and Huntington\u2019s diseases. This systematic review aimed to evaluate the effects of plant extracts and phytochemicals on NMDAR-mediated excitotoxicity and to summarize their proposed neuroprotective mechanisms. The review protocol was registered in PROSPERO (CRD42024528160). A systematic search of Medline, Embase, Web of Science Core Collection, and PubMed identified 323 records, with an additional 7 records identified through manual searching that specifically considered in vitro and in vivo inhibitors of NMDAR excitotoxicity using plant extracts and isolated phytochemicals. Twenty-seven studies demonstrated that plant extracts and phytochemicals attenuate excitotoxicity through multiple mechanisms, including inhibition of NMDAR-induced currents, reduction of intracellular calcium influx, modulation of NMDAR expression, attenuation of oxidative stress, and mitochondrial dysfunction. However, the evidence base was largely dominated by in vitro and ex vivo studies, with limited in vivo validation, restricting translational relevance. Risk-of-bias assessment using an adapted version of the Office of Health Assessment and Translation (OHAT) Risk of Bias Tool indicated that 4 studies had a low overall risk of bias, 12 had low to moderate risk, and 11 were at moderate risk, with key limitations related to inadequate reporting of blinding, randomization, and allocation concealment. In contrast, exposure characterization, outcome assessment, and confounding control were generally strong across studies. Although the findings support the mechanistic neuroprotective potential of certain plant extracts and phytochemicals against NMDAR-mediated excitotoxicity, further well-designed in vivo and clinical studies are required to establish their therapeutic relevance for the treatment of neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/cimb48060611","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T09:49:51Z","timestamp":1781257791000},"page":"611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phytochemicals as NMDA Receptor Inhibitors and Their Potential for Treating Excitotoxicity-Related Neurotoxicity: A Systematic Review"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2288-089X","authenticated-orcid":false,"given":"Maryam N.","family":"ALNasser","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, College of Science, King Faisal University, P.O. Box No. 400, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1475-2476","authenticated-orcid":false,"given":"Wayne G.","family":"Carter","sequence":"additional","affiliation":[{"name":"Clinical Toxicology Research Group, School of Medicine, Royal Derby Hospital Centre, University of Nottingham, Derby DE22 3DT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1016\/j.neuron.2023.05.002","article-title":"NMDA receptor functions in health and disease: Old actor, new dimensions","volume":"111","author":"Dupuis","year":"2023","journal-title":"Neuron"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"110609","DOI":"10.1016\/j.pnpbp.2022.110609","article-title":"Molecular mechanisms underlying the N-methyl-d-aspartate receptor antagonists: Highlighting their potential for transdiagnostic therapeutics","volume":"119","author":"Driver","year":"2022","journal-title":"Prog. 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