Microglial expression of prostaglandin EP3 receptor in excitotoxic lesions in the rat striatum.
Prostaglandins (PG) are produced by the enzymatic activity of cyclooxygenase (COX). PGs and COX have been implicated in the pathophysiology of excitotoxicity and neurodegeneration in the central nervous system (CNS). The PGE2 receptor EP3 is the most abundantly expressed PGE2 receptor subtype in the brain. So far, in the innate rat brain EP3 receptors have been found exclusively in neurons. The aim of this study was to investigate whether EP3 expression in the brain changes under neurodegenerative circumstances such as an acute excitotoxic lesion. Intrastriatal injection of quinolinic acid (QUIN) resulted in a loss of EP3-positive striatal neurons, while simultaneously small glial-shaped EP3-positive cells appeared. Five days after lesioning, 63% of the glial-shaped EP3-positive cells could be identified as ED-1 expressing microglial cells. This percentage increased to 82% after 10 days, suggesting that most of the EP3-positive ED-1-negative cells on day 5 may be microglia which did not yet express ED-1. ED-1-positive microglia also expressed COX-1. These experiments show for the first time that activated microglial cells in excitotoxic lesions express in vivo the PGE2 receptor EP3 and the PGE2 synthesizing enzyme COX-1. Activation of EP3 receptor downregulates cAMP formation and may counteract the upregulation of cAMP formation via EP2 receptors, which has been linked to the anti-inflammatory effects of PGs. This change in EP3-receptor expression in microglia might participate in acute or chronic microglial activation in a variety of brain diseases such as ischemia or Alzheimer's disease (AD). Investigation of the expression of different PGE2 receptor subtypes might promote a better understanding of the pathophysiology of these diseases as well as leading to a modulation of microglial activation by a more specific interference with selective EP receptors than can be achieved by inhibiting global PG synthesis by selective or non-selective COX inhibitors.
Slawik
H
H
Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstr. 5, D-79104 Freiburg, Germany. helen_slawik@psyallg.ukl.uni-freiburg.de
Volk
B
B
Fiebich
B
B
Hüll
M
M
D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D051545:Cyclooxygenase 1; D018846:Excitatory Amino Acids / Q000008:administration & dosage / Q000633:toxicity*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008845:Microinjections; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013238:Stereotaxic Techniques
D018846:Excitatory Amino Acids; D007527:Isoenzymes; D008565:Membrane Proteins; C545649:Ptger3 protein, rat; D016194:Receptors, N-Methyl-D-Aspartate; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D017378:Quinolinic Acid