CYCLOOXYGENASE-2 EXPRESSION IN RAT MICROGLIA IS INDUCED BY ADENOSINE A(2A)-RECEPTORS

We investigated the regulation of COX-2 expression and activity by ade nosine receptors in rat microglial cells. The selective adenosine A(2a )-receptor agonist CGS21680 and the non-selective adenosine A(1)- and At-receptor agonist 5'-N-ethylcarboxiamidoadenosine (NECA) induced an increase in COX-2 mRNA levels and the synthesis of prostaglandin E(2) (PGE(2)). The adenosine A(1)-receptor agonist cyclopentyladenosine (CP A) was less potent, and the adenosine A(3)-receptor-specific agonist N -6-2-(-aminophenylo)ethyladenosine (APNEA) showed only marginal effect s. Microglia expressed adenosine A(1)-, A(2a)-, and A(3)-, but not A(2 b)-receptor mRNAs, whereas astroglial cells expressed adenosine A(2b)- but not A(2a)-receptor mRNA. The adenosine A(2n)-receptor selective a ntagonist 3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine (KF17837) inhibited both CGS21680-induced COX-2 expression and PGE(2) release. CGS21680-increased PGE(2) levels were inhibited by dexamethasone, by t he nonsteroidal antiinflammatory drug meloxicam, and by the adenylyl c yclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536). CGS21680 and NECA both increased intracellular cAMP levels in microgl ial cells. Dibutyryl cAMP as well as forskolin induced the release of PGE(2). The results strongly suggest that adenosine A(2a)-receptor-ind uced intracellular signaling events cause an up-regulation of the COX- 2 gene and the release of PGE(2). Apparently, the cAMP second messenge r system plays a crucial role in COX-2 gene regulation in rat microgli al cells. The results are discussed with respect to neurodegenerative disorders of the CNS such as Alzheimer's disease, in which activated m icroglia are critically involved and COX inhibitors may be of therapeu tic benefit. (C) 1996 Wiley-Liss, Inc.