THE NEUROPROTECTIVE PEPTIDES <i>PACAP</i> AND <i>ADNP</i> RESCUE CEREBELLAR GRANULE CELLS FROM APOPTOSIS

Neuronal fate is determined by signals that promote either survival or apoptotic death. These signals are essential for the proper development of the central nervous system and the maintenance of homeostasis in adulthood; however, their dysregulation can contribute to the onset of neurological disorders. Through genomic screening and a reverse engineering approach, we previously characterized the transcriptional program regulating apoptosis and survival in cerebellar granule cells (CGCs) deprived of neurotrophic factors. Among the genes analyzed, we identified two transcription factors – Homeobox D9 (Hoxd9) and Nuclear Receptor 4A1 (Nr4a1) – as potential master regulators of the apoptotic process in CGCs cultured under serum deprivation and low potassium conditions (5 mM KCl). In the present study, we investigated the neuroprotective effects of the peptides PACAP and ADNP to assess whether they can prevent neuronal death by modulating the expression of these transcription factors. Using a continuous CGC cell line, we defined the temporal window of neuroprotection for both peptides and evaluated their impact on Hoxd9 and Nr4a1 expression levels. Our findings suggest that Hoxd9 and Nr4a1 may play a pivotal role in the genetic program underlying neuronal survival and represent potential targets for neuroprotective strategies. This study was supported by Unione Europea-Next Generation EU PNRR per Mac2I1.1 (grant number:2022RTBHJ) CUPE53D23015490001.