Activation of EP₂ prostanoid receptors in human glial cell lines stimulates the secretion of BDNF

Prostaglandin E₂ (PGE₂) is produced at high levels in the injured central nervous system, where it is generally considered a cytotoxic mediator of inflammation. The cellular actions of PGE₂ are mediated by G-protein signaling activated by prostanoid receptors termed EP₁, EP₂, EP₃ and EP₄. Recent studies have implicated the EP₂ prostanoid receptor to be in apparently conflicting roles promoting neuronal death in some model systems and the survival of neurons in others. Here we show that treatment of immortalized human microglia and CCF-STTG1 astrocytes with either PGE₂ or the EP₂ selective agonist butaprost stimulates the release of brain-derived neurotrophic factor (BDNF). Both cell lines express mRNA for the EP₂ receptor, whereas transcripts for the other subtypes are not detected. Pharmacological studies using PGE₂ and modulators of cyclic AMP signaling implicate this pathway in PGE₂-stimulated BDNF release. These results indicate that EP₂ prostanoid receptor activation induces BDNF secretion through stimulation of cyclic AMP dependent signaling. Our findings provide a mechanism by which endogenous PGE₂ might contribute to either neurotoxicity or neuroprotection in the injured brain via the induction of BDNF release from microglial cells and astrocytes.