Staurosporine-induced apoptosis in astrocytes is prevented by A1 adenosine receptor activation.
Astrocyte apoptosis occurs in acute and chronic pathological processes at the central nervous system and the prevention of astrocyte death may represent an efficacious intervention in protecting neurons against degeneration. Our research shows that rat astrocyte exposure to 100 nM staurosporine for 3h caused apoptotic death accompanied by caspase-3, p38 mitogen-ed protein kinase (MAPK) and glycogen synthase kinase-3beta (GSK3beta) activation. N(6)-chlorocyclopentyladenosine (CCPA, 2.5-75 nM), a selective agonist of A(1) adenosine receptors, added to the cultures 1h prior to staurosporine, induced a dose-dependent anti-apoptotic effect, which was inhibited by the A(1) receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine. CCPA also caused a dose- and time-dependent phosphorylation/activation of Akt, a downstream effector of cell survival promoting phosphatidylinositol 3-kinase (PI3K) pathway, which in turn led to inhibition of staurosporine-induced GSK3beta and p38 MAPK activity. Accordingly, the anti-apoptotic effect of CCPA was abolished by culture pre-treatment with LY294002, a selective PI3K inhibitor, pointing out the prevailing role played by PI3K pathway in the protective effect exerted by A(1) receptor activation. Since an abnormal p38 and GSK3beta activity is implicated in acute (stroke) and chronic (Alzheimer's disease) neurodegenerative diseases, the results of the present study provide a hint to better understand adenosine relevance in these disorders.
D'Alimonte
Iolanda
I
Department of Biomedical Sciences, G. D'Annunzio University, Chieti, Italy.
Ballerini
Patrizia
P
Nargi
Eleonora
E
Buccella
Silvana
S
Giuliani
Patricia
P
Di Iorio
Patrizia
P
Caciagli
Francesco
F
Ciccarelli
Renata
R
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000187:drug effects* / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D043682:Receptor, Adenosine A1; C048599:N(6)-cyclopentyladenosine; D019869:Phosphatidylinositol 3-Kinases; D019311:Staurosporine; D000241:Adenosine