TY - JOUR
T1 - Induction of COX-2 and reactive gliosis by P2Y receptors in rat cortical astrocytes is dependent on ERK1/2 but independent of calcium signalling
AU - Brambilla, Roberta
AU - Neary, Joseph T.
AU - Cattabeni, Flaminio
AU - Cottini, Lorenzo
AU - D'Ippolito, Gianluca
AU - Schiller, Paul C.
AU - Abbracchio, Maria P.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2002/12
Y1 - 2002/12
N2 - The present study has been aimed at characterizing the ATP/ P2 receptor (and transductional pathways) responsible for the morphological changes induced in vitro by αβmethyleneATP on rat astrocytes obtained from cerebral cortex, a brain area highly involved in neurodegenerative diseases. Exposure of cells to this purine analogue resulted in elongation of cellular processes, an event reproducing in vitro a major hallmark of in vivo reactive gliosis. αβmethyleneATP-induced gliosis was prevented by the P2X/P2Y blocker pyridoxalphosphate-6-azophenyl-2′-4′-disulfonic acid, but not by the selective P2X antagonist 2′,3′-O-(2,4,6-trinitrophenyl)-ATP, ruling out a role for ligand-gated P2X receptors. Conversely, the Gi/Go protein inactivator pertussis toxin completely prevented αβmethyleneATP-induced effects. No effects were induced by αβmethyleneATP on intracellular calcium concentrations. RT-PCR and western blot analysis showed that αβmethyleneATP-induced gliosis involves up-regulation of cyclooxygenase-2 (but not lipooxygenase). Also this effect was fully prevented by pyridoxalphosphate-6-azophenyl-2′-4′-disulfonic acid. Experiments with inhibitors of mitogen-activated protein kinases (MAPK) suggest that extracellular signal regulated protein kinases (ERK)1/2 mediate both cyclooxygenase-2 induction and the associated in vitro gliosis. These findings suggest that purine-induced gliosis involves the activation of a calcium-independent G-protein-coupled P2Y receptor linked to ERK1/2 and cyclooxygenase-2. Based on the involvement of cyclooxygenase-2 and inflammation in neurodegenerative diseases, these findings open up new avenues in the identification of novel biological targets for the pharmacological manipulation of neurodegeneration.
AB - The present study has been aimed at characterizing the ATP/ P2 receptor (and transductional pathways) responsible for the morphological changes induced in vitro by αβmethyleneATP on rat astrocytes obtained from cerebral cortex, a brain area highly involved in neurodegenerative diseases. Exposure of cells to this purine analogue resulted in elongation of cellular processes, an event reproducing in vitro a major hallmark of in vivo reactive gliosis. αβmethyleneATP-induced gliosis was prevented by the P2X/P2Y blocker pyridoxalphosphate-6-azophenyl-2′-4′-disulfonic acid, but not by the selective P2X antagonist 2′,3′-O-(2,4,6-trinitrophenyl)-ATP, ruling out a role for ligand-gated P2X receptors. Conversely, the Gi/Go protein inactivator pertussis toxin completely prevented αβmethyleneATP-induced effects. No effects were induced by αβmethyleneATP on intracellular calcium concentrations. RT-PCR and western blot analysis showed that αβmethyleneATP-induced gliosis involves up-regulation of cyclooxygenase-2 (but not lipooxygenase). Also this effect was fully prevented by pyridoxalphosphate-6-azophenyl-2′-4′-disulfonic acid. Experiments with inhibitors of mitogen-activated protein kinases (MAPK) suggest that extracellular signal regulated protein kinases (ERK)1/2 mediate both cyclooxygenase-2 induction and the associated in vitro gliosis. These findings suggest that purine-induced gliosis involves the activation of a calcium-independent G-protein-coupled P2Y receptor linked to ERK1/2 and cyclooxygenase-2. Based on the involvement of cyclooxygenase-2 and inflammation in neurodegenerative diseases, these findings open up new avenues in the identification of novel biological targets for the pharmacological manipulation of neurodegeneration.
KW - Cyclooxygenase-2
KW - Neurodegenerative diseases
KW - Neuroinflammation
KW - P2Y receptors
KW - Rat cortex
KW - Reactive astrogliosis
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U2 - 10.1046/j.1471-4159.2002.01239.x
DO - 10.1046/j.1471-4159.2002.01239.x
M3 - Article
C2 - 12472883
AN - SCOPUS:18744383029
VL - 83
SP - 1285
EP - 1296
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 6
ER -