Prostaglandin E(2) (PGE(2)) plays an important role in inflammation and neurologic disorders. The neuromodulatory effects of PGE(2) are mediated through regulation of four G-protein-coupled receptors known as EP1, EP2, EP3, and EP4. The goal of the current study was to determine whether EP2 receptor activation protects neurons from acute NMDA-mediated excitotoxicity. To examine the effects of EP2 activation, mice were given an injection of the EP2 receptor-selective agonist butaprost (K (i) = 110 nM for EP2 receptor; K (i) > 10,000 for other prostaglandin receptors) in the cerebral ventricle and then an injection of NMDA in the right striatum. After 48 h, a significant reduction in NMDA-induced lesion volume was observed in groups pretreated with butaprost (1-300 nmol/L), with maximal protection at 100 nmol/L (p < 0.001). To determine if EP2-activated protection was specific to neurons, mouse neuronal cultures were treated with butaprost, and cell viability was analyzed after 24 h of NMDA excitotoxicity. The results showed that butaprost significantly increased neuron survival in a dose-dependent fashion. Furthermore, treatment of primary neurons with butaprost significantly increased cAMP levels (p < 0.001). Together, these data reveal that EP2 receptor stimulation mediates neuroprotection against NMDA excitotoxicity both in vivo and in vitro and that butaprost can limit acute brain damage. Development and testing of specific PGE(2) receptor mimetics could lead to a decrease in side effects associated with anti-inflammatory drugs and could help to fight acute and/or chronic neurologic disorders.