Teresa Taboada-Jara, Marta Ribalta, Fernando Romero-Becerra, Joel Muixí , Aina Bellver-Sanchis, Christian Griñán-Ferré, Carmen Escolano and Mercè Pallàs

https://doi.org/10.3390/ijms27073282

Neurodegenerative diseases such as Alzheimer’s (AD) and Huntington’s (HD) remain
major therapeutic challenges due to limited treatment efficacy. 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 Aβ1-42) and EAK103 (expressing
Ht513) were employed to assess locomotor activity, oxidative stress tolerance, Aβ and Ht
aggregation, and sod-1 gene expression. Several ligands significantly improved movement,
reduced Aβ 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.