Prostaglandin D2 mediates neuronal protection via the DP1 receptor

Cyclo‐oxygenases (COXs) catalyze the first committed step in the synthesis of the prostaglandins PGE2, PGD2, PGF2α, PGI2 and thomboxane A2. Expression and enzymatic activity of COX‐2, the inducible isoform of COX, are observed in several neurological diseases and result in significant neuronal injury. The neurotoxic effect of COX‐2 is believed to occur through downstream effects of its prostaglandin products. In this study, we examined the function of PGD2 and its two receptors DP1 and chemoattractant receptor‐homologous molecule expressed on Th2 cells (CRTH2) (DP2) in neuronal survival. PGD2 is the most abundant prostaglandin in brain and regulates sleep, temperature and nociception. It signals through two distinct G protein‐coupled receptors, DP1 and DP2, that have opposing effects on cyclic AMP (cAMP) production. Physiological concentrations of PGD2 potently and unexpectedly rescued neurons in paradigms of glutamate toxicity in cultured hippocampal neurons and organotypic slices. This effect was mimicked by the DP1‐selective agonist BW245C but not by the PGD2 metabolite 15d‐PGJ2, suggesting that neuroprotection was mediated by the DP1 receptor. Conversely, activation of the DP2 receptor promoted neuronal loss. The protein kinase A inhibitors H89 and KT5720 reversed the protective effect of PGD2, indicating that PGD2‐mediated neuroprotection was dependent on cAMP signaling. These studies indicate that activation of the PGD2 DP1 receptor protects against excitotoxic injury in a cAMP‐dependent manner, consistent with recent studies of PGE2 receptors that also suggest a neuroprotective effect of prostaglandin receptors. Taken together, these data support an emerging and paradoxical neuroprotective role of prostaglandins in the CNS.