Purinergic signaling induces cyclooxygenase-1-dependent prostanoid synthesis in microglia: roles in the outcome of excitotoxic brain injury.
Cyclooxygenases (COX) are prostanoid synthesizing enzymes constitutively expressed in the brain that contribute to excitotoxic neuronal cell death. While the neurotoxic role of COX-2 is well established and has been linked to prostaglandin E(2) synthesis, the role of COX-1 is not clearly understood. In a model of N-Methyl-D-aspartic acid (NMDA) induced excitotoxicity in the mouse cerebral cortex we found a distinctive temporal profile of COX-1 and COX-2 activation where COX-1, located in microglia, is responsible for the early phase of prostaglandin E(2) synthesis (10 minutes after NMDA), while both COX-1 and COX-2 contribute to the second phase (3-24 hours after NMDA). Microglial COX-1 is strongly activated by ATP but not excitatory neurotransmitters or the Toll-like receptor 4 ligand bacterial lipopolysaccharide. ATP induced microglial COX-1 dependent prostaglandin E(2) synthesis is dependent on P2X7 receptors, extracellular Ca(2+) and cytoplasmic phospholipase A2. NMDA receptor activation induces ATP release from cultured neurons leading to microglial P2X7 receptor activation and COX-1 dependent prostaglandin E(2) synthesis in mixed microglial-neuronal cultures. Pharmacological inhibition of COX-1 has no effect on the cortical lesion produced by NMDA, but counteracts the neuroprotection exerted by inhibition of COX-2 or observed in mice lacking the prostaglandin E(2) receptor type 1. Similarly, the neuroprotection exerted by the prostaglandin E(2) receptor type 2 agonist butaprost is not observed after COX-1 inhibition. P2X7 receptors contribute to NMDA induced prostaglandin E(2) production in vivo and blockage of P2X7 receptors reverses the neuroprotection offered by COX-2 inhibition. These findings suggest that purinergic signaling in microglia triggered by neuronal ATP modulates excitotoxic cortical lesion by regulating COX-1 dependent prostanoid production and unveil a previously unrecognized protective role of microglial COX-1 in excitotoxic brain injury.
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, United States of America. joa2006@med.cornell.edu
Josef
J
Anrather
Eduardo F
EF
Gallo
Takayuki
T
Kawano
Marcello
M
Orio
Takato
T
Abe
Camile
C
Gooden
Ping
P
Zhou
Costantino
C
Iadecola
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018920:Coculture Techniques; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D017353:Gene Deletion; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome
D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011453:Prostaglandins; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058486:Receptors, Purinergic P2X7; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate; D052248:Nitric Oxide Synthase Type I; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone