Therapeutic Potential of 2-(2-Benzofuranyl)-2-Imidazoline in Preclinical CNS Models: A Systematic Review of Mechanisms, Disease Models, and Cellular Targets.

Background/Objectives: 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) is a selective imidazoline I2-site ligand that has shown neuroprotective and neuromodulatory effects in preclinical central nervous system (CNS) studies. However, the primary preclinical literature remains fragmented across disease models, outcome types, mechanistic endpoints, and cellular targets, making it difficult to define where its therapeutic-development potential is strongest and how disease- or model-specific functional effects relate to molecular, cellular, tissue, and blood-brain barrier/neurovascular unit (BBB/NVU)-related findings. Methods: This systematic review integrated preclinical evidence from 36 original studies identified in the PubMed, Web of Science, Embase, and Scopus databases through searches last updated on May 19, 2026, to evaluate the strength of evidence for 2-BFI across CNS-related models and to connect functional, molecular, cellular, and neurovascular findings. The evidence categories included ischemic stroke/neurovascular outcomes (n = 13), traumatic CNS injury (n = 2), neuroinflammatory/neurodegeneration-related models (n = 9), behavioral pharmacology (n = 8), and cellular mechanisms (n = 4). Eligible studies were original CNS-related animal, cellular, or behavioral/pharmacological studies that directly evaluated 2-BFI and reported neuroprotective, neurological, cellular, molecular, vascular, inflammatory, neurotransmitter-related, or behavioral outcomes. Findings were synthesized qualitatively, and risk of bias in in vivo animal studies was assessed using SYRCLE's risk-of-bias tool. Results: The most extensive preclinical evidence was found in ischemic stroke and neurovascular injury models, in which 2-BFI attenuated infarct size, neurological deficits, and edema, and suppressed apoptosis-related injury and blood-brain barrier/neurovascular unit (BBB/NVU) disruption. Across models, these effects are best interpreted as modulation of interconnected secondary injury processes involving N-methyl-D-aspartate receptor (NMDAR)/Ca2+-dependent excitotoxicity, oxidative and mitochondrial stress, inflammatory amplification, regulated cell death, and neurovascular destabilization. Evidence from traumatic CNS injury, autoimmune neuroinflammation, Alzheimer's disease-related models, chronic epilepsy, and cellular stress models broadened the CNS relevance of 2-BFI but remained less replicated or more mechanistically indirect than the stroke/neurovascular evidence. Behavioral and pharmacological studies additionally indicated that 2-BFI modulates neurotransmitter-related systems associated with pain-, affective-, addiction-, opioid-, and compulsivity-related outcomes, although these findings should be distinguished from disease-modifying neuroprotective evidence. Conclusions: Meta-analysis was not conducted because of heterogeneity in models, dosing regimens, treatment timing, and outcomes. Overall, the current evidence does not yet support definitive dosing, treatment timing, or clinical development recommendations for 2-BFI. The strongest preclinical therapeutic rationale is currently found in ischemic stroke and neurovascular injury settings, whereas other CNS indications require further validation. Future studies should define dose-response relationships, therapeutic windows, pharmacokinetic and safety profiles, sex- and age-related effects, and efficacy in clinically relevant comorbid models before clinical translation is considered. The review was not prospectively registered. Funding was provided by a National Research Foundation of Korea grant funded by the Korean government.