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Imidazoline I2 receptor (I2-IR) ligands have recently emerged as promising neuroprotective agents, with reported roles in modulating oxidative stress, neuroinflammation, and protein aggregation. This study evaluates the therapeutic potential of several I2-IR ligands, including Idazoxan, CR4056, and novel compounds, using Caenorhabditis elegans (C. elegans) models of AD and HD. Transgenic strains CL2006 (expressing human A\u03b21-42) and EAK103 (expressing Ht513) were employed to assess locomotor activity, oxidative stress tolerance, A\u03b2 and Ht aggregation, and sod-1 gene expression. Several ligands significantly improved movement, reduced A\u03b2 and Ht aggregates, and enhanced antioxidant gene expression, particularly Idazoxan, LSL42, and PIP01. Notably, some compounds exhibited prooxidant effects, highlighting the utility of C. elegans for early in vivo toxicity screening. Importantly, this study provides the first in vivo evidence of the efficacy of I2-IR ligands in HD models and reinforces their potential as therapeutic candidates for HD. Overall, these findings suggest a potential role for modulation of I2-IR-related pathways in neurodegeneration and support the utility of C. elegans as a rapid, cost-effective platform for preclinical drug evaluation.<\/jats:p>","DOI":"10.3390\/ijms27073282","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T02:06:21Z","timestamp":1775441181000},"page":"3282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Usefulness of C. elegans Models of Alzheimer\u2019s and Huntington\u2019s Disease to Evaluate Novel Imidazoline I2 Receptor Ligands"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9666-333X","authenticated-orcid":false,"given":"Teresa","family":"Taboada-Jara","sequence":"first","affiliation":[{"name":"Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neuroci\u00e8ncies (UBNeuro), University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Ribalta","sequence":"additional","affiliation":[{"name":"Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neuroci\u00e8ncies (UBNeuro), University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Romero-Becerra","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. 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