Cyclo-oxygenase-2 mediates P2Y receptor-induced reactive astrogliosis.
Excessive cyclo-oxygenase-2 (COX-2) induction may play a role in chronic neurological 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 astrogliosis. Since COX-2 may be upregulated by AA metabolites, we assessed a possible role for COX-2 in P2Y receptor-mediated astrogliosis. A brief challenge of rat astrocytes with the ATP analogue alpha,beta-methylene ATP (alpha,beta(me)ATP) resulted, 24 h later, in significantly increased COX-2 expression. The selective COX-2 inhibitor NS-398 completely abolished alpha,beta(me)ATP-induced astrocytic activation. Constitutive astroglial COX-1 or COX-2 did not play any role in purine-induced reactive astrogliosis. PGE2, a main metabolite of COX-2, also induced astrocytic activation. These data suggest 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.
Brambilla
R
R
Institute of Pharmacological Sciences, University of Milan, Italy.
Burnstock
G
G
Bonazzi
A
A
Ceruti
S
S
Cattabeni
F
F
Abbracchio
M P
MP
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005911:Gliosis / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D007527:Isoenzymes / Q000187:drug effects / Q000502:physiology*; D009578:Nitrobenzenes / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009578:Nitrobenzenes; D018048:Receptors, Purinergic P2; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000255:Adenosine Triphosphate; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D001241:Aspirin; D015230:Prostaglandin D2