Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino acid containing neuropeptide with various cytoprotective functions including neuroprotection. Administration of PACAP has been shown to reduce damage induced by ischemia, trauma, or exogenous toxic substances. Moreover, mice deficient in PACAP are more vulnerable to damaging insults. In this study, we sought to determine whether PACAP may also be protective against salsolinol-induced toxicity in SH-SY5Y cells and, if so, elucidate its mechanism(s) of action. Salsolinol (SALS) is an endogenous dopamine metabolite with selective toxicity to nigral dopaminergic neurons, which are directly implicated in Parkinson's disease (PD). SH-SY5Y cells, derived from human neuroblastoma cells, express high levels of dopaminergic activity and are used extensively as a model to study these neurons. Exposure of SH-SY5Y cells to 400 μM SALS for 24 h resulted in approximately 50 % cell death that was mediated by apoptosis as determined by cell flow cytometry and increases in caspase-3 levels. Cellular toxicity was also associated with reductions in brain-derived neurotrophic factor and phosphorylated cyclic AMP response element-binding protein. Pretreatment with PACAP dose-dependently attenuated SALS-induced toxicity and the associated apoptosis and the chemical changes. PACAP receptor antagonist PACAP6-38, in turn, dose-dependently blocked the effects of PACAP. Neither PACAP nor PACAP antagonist had any effect of its own on cellular viability. These results suggest the protective effects of PACAP in a cellular model of PD. Hence, PACAP or its agonists could be of therapeutic benefit in PD.