Prostaglandin D2 mediates neuronal protection via the DP1 receptor
Open Access
- 14 December 2004
- journal article
- Published by Wiley in Journal of Neurochemistry
- Vol. 92 (3), 477-486
- https://doi.org/10.1111/j.1471-4159.2004.02870.x
Abstract
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.Keywords
This publication has 64 references indexed in Scilit:
- PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosisAnnals of Neurology, 2004
- Neuronal overexpression of cyclooxygenase‐2 increases cerebral infarctionAnnals of Neurology, 2003
- 15-Deoxy-Δ12,14-prostaglandin J2, a specific ligand for peroxisome proliferator-activated receptor-γ, induces neuronal apoptosisNeuroReport, 2001
- Prostaglandin DP receptors positively coupled to adenylyl cyclase in embryonic bovine tracheal (EBTr) cells: pharmacological characterization using agonists and antagonistsBritish Journal of Pharmacology, 1999
- Discovery of Three Novel Orphan G-Protein-Coupled ReceptorsGenomics, 1999
- Profile of prostaglandin levels in the rat hippocampus in pilocarpine model of epilepsyNeurochemistry International, 1995
- Eicosanoids in Rat Brain during Ischemia and Reperfusion—Correlation to DC DepolarizationJournal of Cerebral Blood Flow & Metabolism, 1990
- Formation and Function of Eicosanoids in the Central Nervous SystemAnnals of the New York Academy of Sciences, 1989
- K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinasesBiochemical and Biophysical Research Communications, 1986
- Prostaglandin D2 in rat brain, spinal cord and pituitary: Basal level and regional distributionLife Sciences, 1982