A Neuroprotective Target in the Shadows: A Scoping Review on the Implications of Pharmacological Gaps in σ1R

This scoping review was designed to address the following questions: (1) How has σ1R agonism been conceptualized and investigated as a neuroprotective strategy in the context of glutamate-induced neurotoxicity across preclinical and translational research? (2) What pharmacological characteristics and mechanistic pathways have been most consistently associated with reported neuroprotective effects? and (3) What translational gaps have limited the progression of σ1R agonists from experimental models to clinical application? The population of interest encompassed systems studied with in vitro/in vivo and limited clinical contexts. The contextual focus included neurodegenerative and neuropsychiatric disease models, ligand development strategies, and temporal and collaborative trends within the literature, all with a comparative framing. By explicitly mapping these elements, this scoping review aims to clarify the current state of σ1R research, including persistent limitations, and identify priority areas for future investigation.