{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:09:39Z","timestamp":1788768579204,"version":"build-2803163510"},"reference-count":286,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"\n Introduction<\/jats:title>\n Glutamate\u2010induced neurotoxicity is a shared pathological mechanism across neurodegenerative and neuropsychiatric disorders, but the mechanistic contributions of the sigma\u20101 receptor remain unsolved and underappreciated.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n This scoping review focuses on the pharmacological gaps in \u03c31R agonists by synthesizing mechanistic and bibliometric trends across the most influential literature in the field currently. To map how \u03c31R agonism has historically been thought of and where mechanistic blind spots still persist, we analyzed the top 100 most cited articles from Web of Science, Scopus, and Google Scholar. This approach was grounded in established scientometric methodology for capturing dominant scientific findings and research trajectories, using a PICO\u2010structured framework and evaluating how \u03c31R agonists influence and modulate glutamate\u2010induced excitotoxicity compared with non\u2010\u03c31R interventions, focusing on neuroprotection, calcium regulation, mitochondrial stability, and translational readiness.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Although several agonists like PRE\u2010084, pridopidine, SA4503 and other neurosteroids show mechanistic convergence on ER-mitochondria signaling and calcium homeostasis, citation patterns reveal substantial gaps. These gaps include limited post\u20102015 mechanistic studies and preclinical bottlenecks that have impeded clinical translation.<\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n Despite convergent mechanisms among several agonists, progress toward clinical translation remains limited by challenges in ligand specificity and model fidelity, and the predominance of preclinical evidence. Addressing these limitations may facilitate the development of \u03c31R-targeted therapies for neurodegenerative and other neurological disorders characterized by disrupted calcium signaling and glutamatergic dysfunction.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fphar.2026.1829506","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T07:39:27Z","timestamp":1788766767000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A neuroprotective target in the shadows: a scoping review of pharmacological gaps in \u03c31R agonists for glutamate-induced neurotoxicity"],"prefix":"10.3389","volume":"17","author":[{"given":"Alexa Q.","family":"Xiang","sequence":"first","affiliation":[{"name":"Academy Program, The Ohio State University","place":["Columbus, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison","family":"Thalmann","sequence":"additional","affiliation":[{"name":"Department of Psychology, Kean University","place":["Union, NJ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izna","family":"Khanna","sequence":"additional","affiliation":[{"name":"Saratoga High School","place":["Saratoga, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrishti","family":"Harish","sequence":"additional","affiliation":[{"name":"Mountain House High School","place":["Mountain House, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihir","family":"Khanna","sequence":"additional","affiliation":[{"name":"Wissahickon High School","place":["Ambler, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarush","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Heritage High School","place":["Wake Forest, NC, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leqing","family":"Chen","sequence":"additional","affiliation":[{"name":"Lowell High School","place":["San Francisco, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1007\/s10787-025-10231-4","article-title":"Sigma-1 receptor activation by fluvoxamine ameliorates ER stress, synaptic dysfunction and behavioral deficits in a ketamine model of schizophrenia","volume":"20","author":"Ahmed","year":"2025","journal-title":"Inflammopharmacology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.brainresbull.2011.03.019","article-title":"Sigma-1 receptor ligand PRE-084 reduced infarct volume, neurological deficits, pro-inflammatory cytokines and enhanced anti-inflammatory cytokines after embolic stroke in rats","volume":"85","author":"Allahtavakoli","year":"2011","journal-title":"Brain Res. 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