Investigating the therapeutic potential of natural compounds in Down syndrome: effects of early treatment with polydatin or astaxanthin on neurodevelopmental alterations in the Ts65Dn mouse model

Down syndrome (DS), a genetic condition caused by the triplication of human chromosome 21 (HSA21), is always associated with intellectual disability (ID), originated by precocious neurogenesis impairment, dendritic pathology, characterized by dendritic hypotrophy and reduced spine density, and increased cerebral oxidative stress (OS). There are no therapies for ID in DS. The polyphenol Polydatin (Poly) had shown neuroprotective properties, the ability to cross the brain blood barrier (BBB) and a high bioavailability. The carotenoid Astaxanthin (AST) had shown to improve neurogenesis and cognitive functions primarily through its antioxidant activity, exerted directly, scavenging reactive oxygen species (ROS), and indirectly, modulating pathways involved in the regulation of OS, such as the NRF2 signaling, altered in DS at adult life stages. Since AST has a high chemical instability and low bioavailability, an innovative strategy was to insert this molecule into stealth solid lipid nanoparticles (AST-SSLNs) able to stabilize AST and increase its systemic residence time. Given these premises, this thesis aimed to assess in the Ts65Dn mouse model of DS whether: neonatal treatment with Poly is able to improve hippocampal development and, if a more prolonged treatment, is able to enhance hippocampus-dependent memory; there is a precocious alteration of the antioxidant NRF2 pathway in the hippocampus; neonatal treatment with AST-SSLNs can modulate the NRF2 pathway, reduce OS and improve hippocampal development. Results revealed that in the Ts65Dn mice early treatment with Poly promoted hippocampal neurogenesis and dendritic maturation, normalized the levels of cyclin D1 and DSCAM, and restored hippocampus-dependent memory. The NRF2 pathway was found impaired in neonate Ts65Dn mice, and neonatal treatment with AST-SSLNs was able to activate this signaling, reduce OS, and restore hippocampal neurogenesis and spinogenesis.These findings highlight the potential therapeutic role of Poly and AST vehiculated with nanoparticles for the amelioration of hippocampal development.