{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:11:21Z","timestamp":1785424281759,"version":"3.56.0"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014188","name":"National Research Foundation of Korea (NRF) grant funded by the Korea government","doi-asserted-by":"publisher","award":["RS-2025-23963199"],"award-info":[{"award-number":["RS-2025-23963199"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2025-23963199"],"award-info":[{"award-number":["RS-2025-23963199"]}],"id":[{"id":"https:\/\/ror.org\/01wpjm123","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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\u2013brain 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\u2019s 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\u2013brain 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\u2019s 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\u2013response 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.<\/jats:p>","DOI":"10.3390\/ph19081155","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:26:23Z","timestamp":1785115583000},"page":"1155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Therapeutic Potential of 2-(2-Benzofuranyl)-2-Imidazoline in Preclinical CNS Models: A Systematic Review of Mechanisms, Disease Models, and Cellular Targets"],"prefix":"10.3390","volume":"19","author":[{"given":"In-Ae","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Occupational Therapy, Division of Health, Baekseok University, Cheonan-si 31065, Republic of Korea"},{"name":"Department of Rehabilitation Medicine, Konkuk University School of Medicine and Konkuk University Medical Center, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hee","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Konkuk University School of Medicine and Konkuk University Medical Center, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8718-0099","authenticated-orcid":false,"given":"Jongmin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Konkuk University School of Medicine and Konkuk University Medical Center, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Hee","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Medical Science, Konkuk University School of Medicine, Konkuk University, Chungju 27478, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","unstructured":"(2024). GBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol., 23, 344\u2013381."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41392-024-01911-3","article-title":"Recent advances in Alzheimer\u2019s disease: Mechanisms, clinical trials and new drug development strategies","volume":"9","author":"Zhang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_3","unstructured":"(2024). GBD 2021 Stroke Risk Factor Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol., 23, 973\u20131003."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1146\/annurev.pa.36.040196.002455","article-title":"Imidazoline receptors and their endogenous ligands","volume":"36","author":"Regunathan","year":"1996","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1124\/pr.118.016311","article-title":"Imidazoline Receptor System: The Past, the Present, and the Future","volume":"72","author":"Bousquet","year":"2020","journal-title":"Pharmacol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.pharmthera.2017.03.009","article-title":"Imidazoline I(2) receptors: An update","volume":"178","author":"Li","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.brainres.2010.09.029","article-title":"2-(-2-benzofuranyl)-2-imidazoline induces Bcl-2 expression and provides neuroprotection against transient cerebral ischemia in rats","volume":"1361","author":"Han","year":"2010","journal-title":"Brain Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.4103\/1673-5374.241461","article-title":"2-(2-Benzofuranyl)-2-imidazoline treatment within 5 hours after cerebral ischemia\/reperfusion protects the brain","volume":"13","author":"Zhang","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1016\/j.jstrokecerebrovasdis.2017.12.041","article-title":"2-(2-Benzofuranyl)-2-Imidazoline Mediates Neuroprotection by Regulating the Neurovascular Unit Integrity in a Rat Model of Focal Cerebral Ischemia","volume":"27","author":"Zhang","year":"2018","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.bbrc.2012.06.152","article-title":"Neurovascular protection conferred by 2-BFI treatment during rat cerebral ischemia","volume":"424","author":"Han","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"149284","DOI":"10.1016\/j.brainres.2024.149284","article-title":"2-BFI protects against ischemic stroke by selectively acting on NR2B-containing NMDA receptors","volume":"1845","author":"Xu","year":"2024","journal-title":"Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.brainresbull.2021.06.016","article-title":"The 2-(2-benzofuranyl)-2-imidazoline provides neuroprotection against focal cerebral ischemia-reperfusion injury in diabetic rats: Influence of microglia and possible mechanisms of action","volume":"174","author":"Xi","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"135766","DOI":"10.1016\/j.neulet.2021.135766","article-title":"2-BFI attenuates ischemic injury by modulating mTOR signaling and neuroinflammation in rats","volume":"750","author":"Cheng","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"586","DOI":"10.31083\/ph.2020.0634","article-title":"2-(-2-Benzofuranyl)-2-imidazoline reciprocally regulates Th17\/Treg balance induced by ischemic stroke in rats","volume":"75","author":"Huang","year":"2020","journal-title":"Pharmazie"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.brainres.2018.08.027","article-title":"Protective effects of 2-(2-benzonfuranyl)-2-imidazoline combined with tissue plasminogen activator after embolic stroke in rats","volume":"1699","author":"Guo","year":"2018","journal-title":"Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, L., Xu, S., Wu, X., Chen, J., Guo, X., Cao, Y., Zhang, Z., Yan, J., Cheng, J., and Han, Z. (2020). Combined Treatment with 2-(2-Benzofu-Ranyl)-2-Imidazoline and Recombinant Tissue Plasminogen Activator Protects Blood-Brain Barrier Integrity in a Rat Model of Embolic Middle Cerebral Artery Occlusion. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00801"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lin, X., Zhu, J., Ni, H., Rui, Q., Sha, W., Yang, H., Li, D., and Chen, G. (2019). Treatment with 2-BFI Attenuated Spinal Cord Injury by Inhibiting Oxidative Stress and Neuronal Apoptosis via the Nrf2 Signaling Pathway. Front. Cell. Neurosci., 13.","DOI":"10.3389\/fncel.2019.00567"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ni, H., Rui, Q., Lin, X., Li, D., Liu, H., and Chen, G. (2019). 2-BFI Provides Neuroprotection Against Inflammation and Necroptosis in a Rat Model of Traumatic Brain Injury. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00674"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1007\/s11064-014-1502-0","article-title":"Brain protection conferred by long-term administration of 2-(2-benzofuranyl)-2-imidazoline against experimental autoimmune encephalomyelitis","volume":"40","author":"Zhu","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.bbrc.2011.02.018","article-title":"2-BFI attenuates experimental autoimmune encephalomyelitis-induced spinal cord injury with enhanced B-CK, CaATPase, but reduced calpain activity","volume":"406","author":"Wang","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1007\/s11064-021-03304-2","article-title":"2-(2-Benzofuranyl)-2-Imidazoline Attenuates the Disruption of the Blood-Brain Barrier in EAE via NMDAR","volume":"46","author":"Xia","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1038\/sj.bjp.0706019","article-title":"Locomotor effects of imidazoline I2-site-specific ligands and monoamine oxidase inhibitors in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway","volume":"143","author":"Macinnes","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"178916","DOI":"10.1016\/j.ejphar.2026.178916","article-title":"Agmatine interaction with imidazoline receptor inhibits manifestation of depression-like behavior in 3-Nitropropionic acid-induced Huntington\u2019s disease-like phenotype in rats","volume":"1025","author":"Katariya","year":"2026","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.brainresbull.2020.04.013","article-title":"Agmatine ameliorates manifestation of depression-like behavior and hippocampal neuroinflammation in mouse model of Alzheimer\u2019s disease","volume":"160","author":"Kotagale","year":"2020","journal-title":"Brain Res. Bull."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neures.2017.10.010","article-title":"The protective effect of 2-(2-benzonfu-ranyl)-2-imidazoline against oxygen-glucose deprivation in cultured rat cortical astrocytes","volume":"133","author":"Tian","year":"2018","journal-title":"Neurosci. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"385","DOI":"10.3233\/JIN-170032","article-title":"2-(2-benzofuranyl)-2-imidazoline (2-BFI) improved the impairments in AD rat models by inhibiting oxidative stress, inflammation and apoptosis","volume":"16","author":"Tian","year":"2017","journal-title":"J. Integr. Neurosci."},{"key":"ref_27","first-page":"9","article-title":"2-BFI inhibits hippocampal neuron apoptosis and NMDA receptor expression in chronic epileptic rats","volume":"9","author":"Tu","year":"2016","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"172976","DOI":"10.1016\/j.pbb.2020.172976","article-title":"Agmatine reverses memory deficits induced by Abeta(1)(-)(42) peptide in mice: A key role of imidazoline receptors","volume":"196","author":"Kotagale","year":"2020","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"172779","DOI":"10.1016\/j.pbb.2019.172779","article-title":"Agmatine reverses ethanol consumption in rats: Evidences for an interaction with imidazoline receptors","volume":"186","author":"Taksande","year":"2019","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ejphar.2014.02.045","article-title":"Imidazoline binding sites mediates anticompulsive-like effect of agmatine in marble-burying behavior in mice","volume":"732","author":"Dixit","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1111\/bph.14161","article-title":"Mechanisms of imidazoline I(2) receptor agonist-induced antinociception in rats: Involvement of monoaminergic neurotransmission","volume":"175","author":"Siemian","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1111\/acer.13972","article-title":"Agmatine Inhibits Behavioral Sensitization to Ethanol Through Imidazoline Receptors","volume":"43","author":"Taksande","year":"2019","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.pnpbp.2011.11.005","article-title":"The potential antidepressant-like effect of imidazoline I2 ligand 2-BFI in mice","volume":"37","author":"Tonello","year":"2012","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/sj.bjp.0702031","article-title":"Attenuation of tolerance to opioid-induced antinociception and protection against morphine-induced decrease of neurofilament proteins by idazoxan and other I2-imidazoline ligands","volume":"125","author":"Boronat","year":"1998","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/sj.bjp.0705052","article-title":"Attenuation of acute and chronic effects of morphine by the imidazoline receptor ligand 2-(2-benzofuranyl)-2-imidazoline in rat locus coeruleus neurons","volume":"138","author":"Torrecilla","year":"2003","journal-title":"Br. J. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.alcohol.2019.09.002","article-title":"Inhibitory influence of agmatine in ethanol withdrawal-induced depression in rats: Behavioral and neurochemical evidence","volume":"83","author":"Chimthanawala","year":"2020","journal-title":"Alcohol"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Parker, C.A., Nutt, D.J., and Tyacke, R.J. (2023). Imidazoline-I2 PET Tracers in Neuroimaging. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24129787"},{"key":"ref_38","first-page":"n71.39","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s11064-022-03781-z","article-title":"2-BFI Provides Neuroprotection Against Fluorosis by Stabilizing Endoplasmic Reticulum-Mitochondria Contact Sites and Inhibiting Activation of the NLRP3 Inflammasome","volume":"48","author":"Chen","year":"2023","journal-title":"Neurochem. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1016\/j.bbrc.2018.08.086","article-title":"Protective effect of the imidazoline I2 receptor agonist 2-BFI on oxidative cytotoxicity in astrocytes","volume":"503","author":"Choi","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1177\/0269881112450785","article-title":"Chronic treatment with selective I2-imidazoline receptor ligands decreases the content of pro-apoptotic markers in rat brain","volume":"27","author":"Garau","year":"2013","journal-title":"J. Psychopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1179\/174313209X444116","article-title":"Attenuation of ischemia-induced rat brain injury by 2-(-2-benzofuranyl)-2-imidazoline, a high selectivity ligand for imidazoline I(2) receptors","volume":"31","author":"Han","year":"2009","journal-title":"Neurol. Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Han, Z., Yang, J.L., Jiang, S.X., Hou, S.T., and Zheng, R.Y. (2013). Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2-BFI confers neuroprotection. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064894"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejphar.2009.11.063","article-title":"Reversible inhibition of intracellular calcium influx through NMDA receptors by imidazoline I(2) receptor antagonists","volume":"629","author":"Jiang","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/PL00004911","article-title":"[3H]2-(2-Benzofuranyl)-2-imidazoline, a highly selective radioligand for I2-imidazoline receptor binding sites. Studies in rabbit kidney membranes","volume":"355","author":"Hosseini","year":"1997","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1155\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:26:48Z","timestamp":1785115608000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1155"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ph19081155"],"URL":"https:\/\/doi.org\/10.3390\/ph19081155","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]}}}