Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors

✍ Scribed by Bernd L. Fiebich; Knut Biber; Klaus Lieb; Dietrich Van Calker; Mathias Berger; Joachim Bauer; Peter J. Gebicke-Haerter

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 984 KB
• Volume: 18
• Category: Article
• ISSN: 0894-1491
• DOI: 10.1002/(sici)1098-1136(199610)18:2<152::aid-glia7>3.0.co;2-2

✦ Synopsis

We investigated the regulation of COX-2 expression and activity by adenosine receptors in rat microglial cells. The selective adenosine A,,-receptor agonist CGS21680 and the non-selective adenosine Al-and A,-receptor agonist 5'-N-ethylcarboxiamidoadenosine (NECA) induced a n increase in COX-2 mRNA levels and the synthesis of prostaglandin E, (PGE,). The adenosine Al-receptor agonist cyclopentyladenosine (CPA) was less potent, and the adenosine A3-receptor-specific agonist N6-2-(-aminopheny-1o)ethyladenosine (APNEA) showed only marginal effects. Microglia expressed adenosine Al-, AZa-, and A3-, but not AZb-receptor mRNAs, whereas astroglial cells expressed adenosine A2b-but not A2,-receptor mRNA. The adenosine A,,-receptor selective antagonist (E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) inhibited both CGS21680-induced COX-2 expression and PGE2 release. CGS21680-increased PGE, levels were inhibited by dexamethasone, by the nonsteroidal antiinflammatory drug meloxicam, and by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536). CGS21680 and NECA both increased intracellular cAMP levels in microglial cells. Dibutyryl cAMP as well as forskolin induced the release of PGE,. The results strongly suggest that adenosine A2,-receptor-induced intracellular signaling events cause an up-regulation of the COX-2 gene and the release of PGE2. Apparently, the cAMP second messenger system plays a crucial role in COX-2 gene regulation in rat microglial cells. The results are discussed with respect to neurodegenerative disorders of the CNS such as Alzheimer's disease, in which activated microglia are critically involved and COX inhibitors may be of therapeutic benefit. o 1996 Wiley-Liss, Inc.