GSK-3 beta inhibition and prevention of mitochondrial apoptosis inducing factor release are not involved in the antioxidant properties of SB-415286.
The antioxidant effects of lithium and SB-415286, two glycogen synthase kinase-3 beta (GSK-3 beta) inhibitors, were studied in cerebellar granule neurons by measuring changes in 2, 7-dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescence. GSK-3 beta inhibitors inhibit apoptosis mediated by serum and potassium withdrawal (S/K withdrawal) and GSK-3 beta activation, as measured by beta-catenin degradation. Furthermore, as both drugs prevent mitochondrial apoptosis inducing factor (AIF) release, these data indicate that GSK-3 beta inhibitors prevent caspase-independent apoptosis in cerebellar granule neurons induced by S/K withdrawal. While the most specific GSK-3 beta inhibitor, SB-415286, demonstrated antioxidant effects, Li+ 10 mM did not. These results indicate that lithium 10 mM and SB-415286 20 microM exert anti-apoptotic effects in cases of S/K withdrawal mediated by GSK-3 beta inhibition. However, these antioxidant properties are independent of GSK-3 beta inhibition and prevention of mitochondrial AIF release.
Yeste-Velasco
Marc
M
Unitat de Farmacologia i Farmacognòsia and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain.
Folch
Jaume
J
Jiménez
Andres
A
Rimbau
Victor
V
Pallàs
Mercè
M
Camins
Antoni
A
D000627:Aminophenols / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D008094:Lithium / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D000627:Aminophenols; D000975:Antioxidants; D051033:Apoptosis Inducing Factor; D008301:Maleimides; D018696:Neuroprotective Agents; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3