A novel gliotic P2 receptor mediating cyclooxygenase-2 induction in rat and human astrocytes

In astrocytic cultures maintained in vitro, a brief challenge with the ATP analog alpha,beta methyleneATP (alpha,beta meATP) results, 3 days later, in marked elongation of astrocytic processes, an event that resembles the ast rocytic hypertrophy known to occur in vivo during reactive astrogliosis. al pha,beta meATP-induced effects were observed in primary astrocytes obtained from both rat striatum and cortex (a brain area highly involved in chronic neurodegenerative pathologies), as well as in human astrocytoma cells (ADF cells). Purine-induced gliosis could be reversed by the non-selective P2X/ P2Y receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic ac id (PPADS), but not by oxidized ATP (an antagonist of the P2X(7) receptor), in line with previous studies of our laboratory suggesting the involvement of a P2Y receptor subtype. Induction of reactive gliosis was preceded by i ncreased expression of cyclooxygenase-2 (COX-2), an enzyme whose excessive activation has been implicated in both acute and chronic neurodegenerative diseases. The selective COX-2 inhibitor NS-398 prevented both purine-induce d astrogliosis and the associated COX-2 induction, suggesting that inhibiti on of the transcription of the COX-2 gene may also contribute to the anti-i nflammatory properties of this agent. Significant blockade of both alpha,be ta meATP-mediated reactive gliosis and COX-2 induction was also observed wi th PPADS. These data suggest that COX-2 mediates P2Y receptor-induced react ive astrogliosis, and that antagonists selective for this receptor subtype may represent a novel class of anti-inflammatory agents of potential intere st in acute and chronic neurological disorders characterized by an inflamma tory component and reactive gliosis. (C) 2000 Elsevier Science B.V. All rig hts reserved.