Induction of COX-2 and reactive gliosis by P2Y receptors in rat cortical astrocytes is dependent on ERK1/2 but independent of calcium signalling

Roberta Brambilla, Joseph T. Neary, Flaminio Cattabeni, Lorenzo Cottini, Gianluca D'Ippolito, Paul C. Schiller, Maria P. Abbracchio

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1285-1296
Number of pages12
JournalJournal of neurochemistry
Volume83
Issue number6
DOIs
StatePublished - Dec 1 2002

Keywords

  • Cyclooxygenase-2
  • Neurodegenerative diseases
  • Neuroinflammation
  • P2Y receptors
  • Rat cortex
  • Reactive astrogliosis

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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