Peroxisome proliferator activated receptor gamma (PPARγ) as a therapeutic target for improvement of cognitive performance in Fragile-X

Abstract Rare disorders leading to intellectual disability, such as Fragile X syndrome (FXS) alter synaptic plasticity. Ligand identification of orphan nuclear receptors has led to the discovery of many signaling pathways and has revealed a direct link of nuclear receptors with human conditions such as mental retardation and neurodegenerative diseases. PPARγ agonists can act as neuroprotective agents, promoting synaptic plasticity and neurite outgrowth. Therefore, selective PPARγ agonists are good candidates for therapeutic evaluation in intellectual disabilities. Preliminary results suggest that PPARγ agonists such as Pioglitazone, Rosiglitazone and synthetic agonist, GW1929, are used as the therapeutic agent in neurological disorders. These components interact with intracellular transduction signals (e.g. GSK3β, PI3K/Akt, Wnt/β-Catenin, Rac1 and MMP-9). It seems that interaction with these pathways can improve memory recognition in FXS animal models. The present hypothesis consists of enhancing synaptic plasticity that may then rescue the learning and memory in FXS. This will open many new therapeutic avenues for a variety of human diseases.