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 alpha,beta methyleneATP (
alpha,beta meATP) 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
alpha,beta meATP-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
alpha,beta meATP 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
alpha,beta meATP 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.