Vasoactive intestinal peptide has neurotrophic and neuroprotective properties that influence the survival of activity-dependent neurons in the central nervous system. Investigations of the mechanism of this neurotrophic peptide indicated that these actions are contingent on interactions with astroglia. The complex mixture of neurotrophic mediators released from astroglia include cytokines, a protease inhibitor, and activity-dependent neurotrophic factor, a protein with apparent structural similarities to hsp60. Investigations of ADNF resulted in the discovery of active peptides of extraordinary potency and broad neuroprotective properties. These studies indicate that a nine-amino acid core peptide of ADNF had significantly greater neuroprotective properties in comparison to the parent growth factor and these advantages identify ADNF-9 as an attractive lead compound for drug development.