Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 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 Aβ 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. The online version of this article (10.1007/s13311-018-00681-5) contains supplementary material, which is available to authorized users.