Protective effects of PACAP against lactacystin-induced PC12 cell apoptosis due to prevention of mitochondrial damage and endoplasmic reticulum stress

Background: Pituitary Adenylate Cyclase Activating Peptide (PACAP) has a significant protective effect on nerve cell damage induced by several neurotoxins. The ubiquitin proteasome inhibitor lactacystin, one new neurotoxin, could cause cell damage by inducing dopaminergic cells apoptosis. Whether PACAP has a protective effect on lactacystin-induced cytotoxic model has not been reported.Aims: The present study was designed to explore whether PACAP can effectively inhibit the lactacystininduced dopaminergic apoptosis.Methods: Pheochromocytes (PC12 cells) differentiated by nerve growth factor as neurons were treated with lactacystin (20 μmol/l) for 24 h, to establish the Parkinsonu0027s disease cells model. Groups are set up as control group, lactacystin group, PACAP1-27 intervention group, PACAP1-27 and PACAP6-27 cointervention group.Results: Treatment with lactacystin can make the cell vitality obviously decline. Compared with control group, cell morphology presented obviously damaged change in lactacystin group. After treatment with lactacystin, the expression of mitochondrial bcl-2 dramaticly decreased, expression of mitochondrial bax had no change, the rate of bcl-2/bax dramaticly decreased, and thus expression of caspase-3 increased. Meanwhile, caspase-12, the characteristic marker of endoplasmic reticulum stress, increased significantly in lactacystin group. However, these changes could be partly reversed by treatment with PACAP1-27. This protective effect of PACAP1-27 was negated by PACAP6-27, a receptor antagonist of PACAP1-27.Conclusion: Lactacystin led to cell damage by inducing mitochondrial damage and endoplasmic reticulum stress; PACAP1-27 played a protective role by regulating the mitochondrial and endoplasmic reticulum related dual signal pathway. As one PACAP1-27 receptor antagonist, PACAP6-27 attenuated this effect of PACAP1-27.