A neuroprotective target in the shadows: a scoping review of pharmacological gaps in σ1R agonists for glutamate-induced neurotoxicity

Introduction Glutamate‐induced neurotoxicity is a shared pathological mechanism across neurodegenerative and neuropsychiatric disorders, but the mechanistic contributions of the sigma‐1 receptor remain unsolved and underappreciated. Methods This scoping review focuses on the pharmacological gaps in σ1R agonists by synthesizing mechanistic and bibliometric trends across the most influential literature in the field currently. To map how σ1R 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‐structured framework and evaluating how σ1R agonists influence and modulate glutamate‐induced excitotoxicity compared with non‐σ1R interventions, focusing on neuroprotection, calcium regulation, mitochondrial stability, and translational readiness. Results Although several agonists like PRE‐084, 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‐2015 mechanistic studies and preclinical bottlenecks that have impeded clinical translation. Discussion 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 σ1R-targeted therapies for neurodegenerative and other neurological disorders characterized by disrupted calcium signaling and glutamatergic dysfunction.