Modulation of cyclooxygenase-2 and brain reactive astrogliosis by purinergic P2 receptors

Roberta Brambilla, Maria P. Abbracchio

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Astroglial cells respond to trauma and ischemia with reactive gliosis, a reaction characterized by increased astrocytic proliferation and hypertrophy. Although beneficial to a certain extent, excessive gliosis may be detrimental, contributing to neuronal death in neurodegenerative diseases. We have tested the hypothesis that ATP may act as a trigger of reactive gliosis in an in vitro model (rat brain primary astrocytes) where reactive astrogliosis can be quantified as elongation of astrocytic processes. Challenge of cells with the ATP analog α,βmethyleneATP (α,βmeATP) resulted in concentration dependent elongation of astrocytic processes, an effect that was fully counteracted by the non-selective ATP/P2 receptor antagonists suramin and pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS). Signalling studies revealed that α,βmeATP-induced gliosis is mediated by a novel G-protein-coupled receptor (a P2Y receptor) coupled to an early release of arachidonic acid. Challenge of cells with α,βmeATP also resulted in an increase of inducible cyclooxygenase-2 (COX-2), the activity of which has been reported to be pathologically increased in a variety of neurodegenerative diseases characterized by inflammation and astrocytic activation. Induction of COX-2 by α,βmeATP was causally related to reactive astrogliosis, since the selective COX-2 inhibitor NS-398 prevented both the purine-induced elongation of astrocytic processes and the associated COX-2 increase. Preliminary data on the putative receptor-to-nucleus pathways responsible for purine-induced gliosis suggest that induction of the COX-2 gene may occur through the protein kinase C/mitogen activated protein kinase system, and may involve the formation of activated AP-1 transcription complexes. We speculate that antagonists selective at this novel P2Y receptor subtype may represent a novel class of neuroprotective agents able to slow down neurodegeneration by counteracting the inflammatory events contributing to neuronal cell death.

Original languageEnglish (US)
Pages (from-to)54-62
Number of pages9
JournalAnnals of the New York Academy of Sciences
Volume939
StatePublished - Jan 1 2001
Externally publishedYes

Keywords

  • ATP
  • Inflammatory gliosis
  • Neurodegenerative diseases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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