Cerebrospinal fluid prostaglandin E 2 (PGE 2 ) levels are elevated in patients with Alzheimer's disease (AD), suggesting an involvement of PGE 2 in the neurodegeneration. AD is characterized by deposits of amyloid β protein (Aβ) in various regions of the brain, e.g. the cerebral cortex. In the present study, we investigated the effects of PGE 2 on neuronal survival in primary cultures of rat cortical neurons. PGE 2 had no effect on neuronal cell viability or its morphology. Therefore, we examined the synergistic effects of PGE 2 with Aβ, a neurotoxin. Aβ caused neuronal cell death via apoptosis. PGE 2 significantly suppressed Aβ neurotoxicity, but did not promote the neurotoxicity. Furthermore, PGE 2 ameliorated Aβ-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Aβ increased the influx of Ca 2 + into neurons before cell death. Nimodipine, an inhibitor of the L-type voltage-sensitive calcium channel (L-VSCC), significantly reduced Aβ-potentiated Ca 2 + uptake. On the other hand, there was no effect on the Aβ-induced Ca 2 + influx by an N-VSCC blocker or P/Q-VSCC blockers. Moreover, the inhibitor of L-VSCC suppressed Aβ-induced neuronal cell death, whereas neither an N-VSCC blocker nor P/Q-VSCC blockers affected the neurotoxicity of Aβ. PGE 2 also suppressed the Aβ-induced Ca 2 + influx in a concentration-dependent manner. This study demonstrated that PGE 2 rescues cortical neurons from Aβ-induced apoptosis by reducing Ca 2 + influx in the primary culture. Furthermore, the present study suggested that the inhibition of L-VSCC contributes to the neuroprotective effect of PGE 2 .