Pituitary adenylate cyclase-activating polypeptide (PACAP) has well-documented neuroprotective actions, which have also been shown in retinal degeneration induced by monosodium glutamate (MSG) in neonatal rats. The aim of this article was to investigate the activation of extracellular signal-regulated kinase (ERK1/2) and cyclic adenosine 3',5'-phosphate (cAMP)-responsive element binding protein (CREB) signaling pathways by Western blot analysis in retinal degeneration induced by MSG. We found that intravitreal administration of PACAP preceding the MSG treatments induced significant increases in the phosphorylation, that is, the activation of ERK1/2 and its downstream target, CREB, 12 h after the treatment compared to the contralateral untreated eye during the first two treatments, with no further elevations 24 h after treatments. These results demonstrate that the degenerative effect of MSG and the protective effect of PACAP involve complex kinase signaling pathways and are related to cAMP/ERK/CREB activation.