Identification of a novel P2 receptor associated with cyclooxygenase-2 upregulation and reactive astrogliosis

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Astrocytes respond to trauma and ischemia with reactive astrogliosis. Although beneficial under certain conditions, excessive gliosis may be detrimental and contribute to neuronal death in neurodegenerative diseases. To evaluate the hypothesis that ATP may act as a trigger of reactive gliosis, we tested α,βmethyleneATP (α,βmeATP) in an in vitro experimental model (rat brain astrocytic cultures), where astrogliosis can be quantified as elongation of astrocytic processes, an event that reproduces one of the main hallmarks of in vivo gliosis, α,βmeATP induced a concentration-dependent elongation of astrocytic processes, an effect which was counteracted by the P2 receptor antagonists suramin and pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS). Signaling studies revealed that α,βmeATP-induced gliosis is mediated by a G-protein-coupled receptor (a P2Y receptor) characterized by an "atypical" pharmacological profile and coupled to an early release of arachidonic acid. In an earlier study we showed that challenge of cells with α,βmeATP also resulted in upregulation of inducible cyclooxygenase-2 (COX-2), whose activity has been reported to be pathologically elevated in neurodegenerative diseases characterized by inflammation and astrocytic activation. Upregulation of COX-2 by α,βmeATP was causally related to reactive astrogliosis in vitro, since the selective COX-2 inhibitor NS-398 prevented both purine-induced elongation of astrocytic processes and the associated increase in COX-2 protein levels. Preliminary data on the putative receptor-to-nucleus pathways responsible for purine-induced gliosis suggest that upregulation of COX-2 may occur through the protein kinase C / mitogen-activated protein kinase system and may involve the formation of AP-1 transcription complexes. We speculate that antagonists selective for this novel P2Y receptor subtype may represent a new class of neuroprotective agents able to reduce neurodegeneration by counteracting the inflammatory events contributing to neuronal cell death.

Original languageEnglish (US)
Pages (from-to)148-157
Number of pages10
JournalDrug Development Research
Volume53
Issue number2-3
DOIs
StatePublished - 2001

Fingerprint

Gliosis
Cyclooxygenase 2
Up-Regulation
Neurodegenerative Diseases
Suramin
Cyclooxygenase 2 Inhibitors
Transcription Factor AP-1
Neuroprotective Agents
G-Protein-Coupled Receptors
Mitogen-Activated Protein Kinases
Arachidonic Acid
Astrocytes
Protein Kinase C
Cell Death
Theoretical Models
Ischemia
Adenosine Triphosphate
Pharmacology
Inflammation
Acids

Keywords

  • ATP
  • Inflammatory gliosis
  • Neurodegenerative diseases

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Identification of a novel P2 receptor associated with cyclooxygenase-2 upregulation and reactive astrogliosis. / Brambilla, Roberta; Schiller, Paul C; D'Ippolito, Gianluca; Neary, Joseph T.; Burnstock, Geoffrey; Cattabeni, Flaminio; Abbracchio, Maria P.

In: Drug Development Research, Vol. 53, No. 2-3, 2001, p. 148-157.

Research output: Contribution to journalArticle

Brambilla, Roberta ; Schiller, Paul C ; D'Ippolito, Gianluca ; Neary, Joseph T. ; Burnstock, Geoffrey ; Cattabeni, Flaminio ; Abbracchio, Maria P. / Identification of a novel P2 receptor associated with cyclooxygenase-2 upregulation and reactive astrogliosis. In: Drug Development Research. 2001 ; Vol. 53, No. 2-3. pp. 148-157.
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