In primary cultures from rat cerebral cortex, pituitary adenylate cyclase-activating polypeptide (PACAP-38) exerted a protective effect on cell death induced by the excitotoxin NMDA in neuron-enriched cultures and also on apoptotic cell death induced by serum deprivation in mixed neuronal-glial cultures. The neuroprotective effect was already observed at subnanomolar concentrations of PACAP and was slightly more pronounced against excitotoxic cell death. BDNF protein expression was reduced by NMDA and much more markedly by serum deprivation (approximately 28 and 93% reduction respectively). In both cellular injury conditions, the diminished BDNF expression was significantly prevented by PACAP. When purified neuronal cultures were preincubated with an antiserum anti-BDNF, at a concentration without any intrinsic effect on cell viability, the neuprotective effect of PACAP was no longer observed. The results suggest that the neuroprotective effect of PACAP-38 is mediated, at least in part, by preventing the suppressed expression of a neurotrophin essential for cortical neuron survival.