KR 31378, a Potent Antioxidant, Inhibits Apoptotic Death of A7r5 Cells

KR 31378, a Potent Antioxidant, Inhibits Apoptotic Death of A7r5 Cells

<P> This work describes the pharmacological inhibition by KR 31378 and its acetyl metabolite, KR 31612, of the apoptotic cell death induced by H<SUB>2</SUB>O<SUB>2</SUB> in the A7r5 cells. Exposure of A7r5 cells to H<SUB>2</SUB>O<SUB>2</SUB> (0.5 mM) induced a concentration-dependent cytotoxicity in association with oligonucleosomal DNA fragmentation. H<SUB>2</SUB>O<SUB>2</SUB>-induced cell death was potently suppressed by KR 31378, KR 31612, α-tocopherol or trolox. Additionally, the apoptotic death of A7r5 cells (DNA ladders on electrophoresis) was also strongly suppressed by KR 31378 and KR 31612, but to a less degree by α-tocopherol and trolox. As a mechanistic study, incubation with H<SUB>2</SUB>O<SUB>2</SUB> markedly showed a decreased Bcl-2 level and, in contrast, increased Bax protein and cytochrome C release, which were significantly and concentration-dependently reversed by KR 31378 and KR 31612 as well as by α-tocopherol and trolox. KR 31378 and α-tocopherol significantly reduced lipid peroxidation in accordance with reduced intracellular ROS and peroxyl radical. These results suggest that KR 31378 has a therapeutic potential against the apoptotic injury via mediation of anti- oxidative stress.