Behavioral and Cognitive Improvement Induced by Novel Imidazoline I-2 Receptor Ligands in Female SAMP8 Mice

Abstract

As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I-2-Imidazoline receptors (I-2-IR) are widely distributed in the central nervous system, and dysregulation of I-2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I-2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I-2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I-2-IR ligands diminished the amyloid precursor protein processing pathway and increased A degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I-2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases.