Cerebral Dopamine Neurotrophic Factor ( <scp>CDNF</scp> ) Acts as a Trophic Factor Promoting Neuritogenesis in the Dorsal Root Ganglia ( <scp>DRG</scp> ) Neurons Through Activation of the <scp>PI3K</scp> Signaling Pathway

The cerebral dopamine neurotrophic factor (CDNF) is a neurotrophic factor extensively studied in the central nervous system because of its neuroprotective effects; however, its role in the peripheral nervous system (PNS) remains less explored. In this study, we used primary dorsal root ganglia (DRG) explants to investigate the neuritogenic potential of exogenous CDNF, as well as its neuroprotective activity under trophic factor deprivation. Our findings demonstrate that CDNF-mediated neuroprotection remains unaffected by the addition of a Trk (tropomyosin receptor kinase) inhibitor or anti-nerve growth factor (NGF) antibody, indicating that CDNF's neurotrophic activity is independent of TrkA signaling. Furthermore, CDNF binding to KDEL-receptor (KDEL-R) was essential for its protective effect, as the CDNF variant lacking the KDEL-R binding sequence (CDNF-ΔKTEL) displayed no significant neuroprotection. Additionally, the simultaneous administration of NGF and CDNF to DRG explants resulted in an additive enhancement of their trophic activities. Notably, both CDNF- and NGF-induced neurotrophic effects were PI3K-dependent, reinforcing the role of this signaling pathway in their mechanisms of action. Taken together, our findings highlight CDNF's crucial role in the PNS, ensuring that NGF-independent neurogenesis can occur. This suggests that CDNF could be further explored in conditions where NGF levels are low or where NGF signaling inhibition is desirable, such as in chronic pain management.