R. Brambilla et al., Identification of a novel P2 receptor associated with cyclooxygenase-2 upregulation and reactive astrogliosis, DRUG DEV R, 53(2-3), 2001, pp. 148-157
Astrocytes respond to trauma and ischemia with reactive astrogliosis. Altho
ugh beneficial under certain conditions, excessive gliosis may be detriment
al and contribute to neuronal death in neurodegenerative diseases. To evalu
ate the hypothesis that ATP may act as a trigger of reactive gliosis, we te
sted alpha,beta methyleneATP (alpha,beta meATP) in an in vitro experimental
model (rat brain astrocytic cultures), where astrogliosis can be quantifie
d as elongation of astrocytic processes, an event that reproduces one of th
e main hallmarks of in vivo gliosis. alpha,beta meATP induced a concentrati
on-dependent elongation of astrocytic processes, an effect which was counte
racted by the P2 receptor antagonists suramin and pyridoxalphosphate-6-azop
henyl-2',4'-disulphonic acid (PPADS). Signaling studies revealed that alpha
,beta meATP-induced gliosis is mediated by a G-protein-coupled receptor (a
P2Y receptor) characterized by an "atypical" pharmacological profile and co
upled to an early release of arachidonic acid. In an earlier study we showe
d that challenge of cells with alpha,beta meATP also resulted in upregulati
on of inducible cyclooxygenase-2 (COX-2), whose activity has been reported
to be pathologically elevated in neurodegenerative diseases characterized b
y inflammation and astrocytic activation. Upregulation of COX-2 by alpha,be
ta meATP was causally related to reactive astrogliosis in vitro, since the
selective COX-2 inhibitor NS-398 prevented both purine-induced elongation o
f 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 thr
ough the protein kinase C / mitogen-activated protein kinase system and may
involve the formation of AP-1 transcription complexes. We speculate that a
ntagonists selective for this novel P2Y receptor subtype may represent a ne
w class of neuroprotective agents able to reduce neurodegeneration by count
eracting the inflammatory events contributing to neuronal cell death. (C) 2
001 Wiley-Liss, Inc.