Cyclo-oxygenase-2 mediates P2Y receptor-induced reactive astrogliosis

Excessive cyclo-oxygenase-2 (COX-2) induction may play a role in chronic ne urological diseases characterized by inflammation and astrogliosis. We have previously identified an astroglial receptor for extracellular nucleotides , a P2Y receptor, whose stimulation leads to arachidonic acid (AA) release, followed, 3 days later, by morphological changes resembling reactive astro gliosis. Since COX-2 may be upregulated by AA metabolites, we assessed a po ssible role for COX-2 in P2Y receptor-mediated astrogliosis. A brief challe nge of rat astrocytes with the ATP analogue alpha,beta-methylene ATP (alpha ,beta meATP) resulted, 24 h later, in significantly increased COX-2 express ion. The selective COX-2 inhibitor NS-398 completely abolished alpha,beta m eATP-induced astrocytic activation. Constitutive astroglial COX-1 or COX-2 did not play any role in purine-induced reactive astrogliosis. PGE(2), a ma in metabolite of COX-2, also induced astrocytic activation. These data sugg est that a P2Y receptor mediates reactive astrogliosis via induction of COX -2. Antagonists selective for this receptor may counteract excessive COX-2 activation in both acute and chronic neurological diseases.