(1) Limited evidence suggests that brain cytosolic phospholipase A2 (cPLA2), which selectively releases arachidonic acid (AA) from membrane phospholipids, and cyclooxygenase-2 (COX-2), the rate-limiting enzyme for AA metabolism to prostanoids, are altered during normal aging. In this study, we examined the protein expression of cPLA2 and COX-2 enzymes in hippocampus, frontal pole and cerebellum from young (2-5 year-old), middle-aged (8-11 year-old) and old (23 year-old) male and female Rhesus monkeys. The cPLA2 protein level was decreased in the cerebellum from both middle-aged and old compared to the young monkeys, whereas the COX-2 protein level was decreased in the frontal pole from both middle-aged and old compared to the young monkeys. Immunohistochemistry in the frontal lobe confirmed fewer COX-2 immunopositive neurons in the old group compared to the young. Based on the localization of cPLA2 and COX-2 at post-synaptic sites in neurons and on evidence of loss of dendritic spines and markers for neurotransmission with aging, these results suggest that the decrease in protein levels of the two enzymes is caused by age-related synaptic dysfunction and that cPLA2 and COX-2 may be considered post-synaptic markers. (2) Only few data are available about COX expression and activity as well as prostaglandin profile during aging. This study aims to determine how these key enzymes in the AA cascade may contribute to the aging process in brain. Our preliminary results indicate an age-related decrease of COX-2 mRNA expression in the hippocampus of 24 and 27 months old rats compared to the young (4 months) and middle aged rats (12 months). However, the upstream enzyme cPLA2 did not show any changes during aging, as the mRNA and protein expression of cPLA2 remained unchanged during aging. Furthermore, we found a significant effect of age on GFAP protein expression in the hippocampus and cerebellum. Further experiments are needed to determine if this age-dependant increase is progressive or not.