In astrocytic cultures maintained in vitro, a brief challenge with the
ATP analog alpha,beta methyleneATP (alpha,betameATP) results, 3 days later, in marked elongation of astrocytic processes, an event that resembles the astrocytic
hypertrophy known to occur in vivo during reactive
astrogliosis.
alpha,beta meATP-induced effects were observed in primary astrocytes obtained from both rat striatum and cortex (a brain area highly involved in chronic neurodegenerative pathologies), as well as in human
astrocytoma cells (ADF cells).
Purine-induced
gliosis could be reversed by the non-selective P2X/P2Y receptor antagonist pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic
acid (
PPADS), but not by
oxidized ATP (an antagonist of the P2X(7) receptor), in line with previous studies of our laboratory suggesting the involvement of a P2Y receptor subtype. Induction of reactive
gliosis was preceded by increased expression of
cyclooxygenase-2 (COX-2), an
enzyme whose excessive activation has been implicated in both acute and chronic
neurodegenerative diseases. The selective
COX-2 inhibitor NS-398 prevented both
purine-induced
astrogliosis and the associated COX-2 induction, suggesting that inhibition of the transcription of the COX-2 gene may also contribute to the anti-inflammatory properties of this agent. Significant blockade of both
alpha,beta meATP-mediated reactive
gliosis and COX-2 induction was also observed with
PPADS. These data suggest that COX-2 mediates P2Y receptor-induced reactive
astrogliosis, and that antagonists selective for this receptor subtype may represent a novel class of
anti-inflammatory agents of potential interest in acute and chronic
neurological disorders characterized by an inflammatory component and reactive
gliosis.