Therapeutic effects of CGS21680, a selective A receptor agonist, via BDNF-related pathways in R106W mutation Rett syndrome model.

Rett syndrome (RTT) is a neurological disorder caused by a mutation in the X-linked methyl-CpG binding protein 2 (MECP2), leading to cognitive and motor skill regression. Therapeutic strategies aimed at increasing brain-derived neurotrophic factor (BDNF) levels have been reported; however, BDNF treatment has limitations, including the inability to penetrate the blood-brain barrier, a short half-life, and potential for adverse effects when administered via intrathecal injection, necessitating novel therapeutic approaches. In this study, we focused on the adenosine A receptor (AR), which modulates BDNF and its downstream pathways, and investigated the therapeutic potential of CGS21680, an AR agonist, through in vitro and in vivo studies using R106W RTT model. CGS21680 restored neurite outgrowth, the number of SYN1/MAP2 puncta pairs, genes related to the BDNF-TrkB signaling pathway (Bdnf, TrkB, and Mtor) and neural development (Tuj1 and Syn1), and electrophysiological functions in in vitro RTT primary neurons. Additionally, CGS21680 alleviated neurobehavioral impairments and modulated gene expression in an RTT in vivo model. Our findings suggest that activation of AR via CGS21680 enhances BDNF-TrkB signaling, which in turn activates downstream pathways, ultimately increasing neurite outgrowth and synaptic plasticity, and restoring neurobehavioral clinical symptoms. This is the first study to report the therapeutic effect of CGS21680 in R106W point mutation RTT models, both in vitro and in vivo. These research results suggest that CGS21680 could be a promising therapeutic candidate for the treatment of RTT.