Posttreatment with the Ca(2+)-Mg(2+)-dependent endonuclease inhibitor aurintricarboxylic acid abolishes genotoxic agent-induced nuclear condensation and DNA fragmentation and decreases death of astrocytes.
DNA fragmentation and nuclear condensation are important nuclear changes in apoptosis. In this study we determined whether DNA fragmentation and nuclear condensation occur in astrocytes treated with 100-200 microM of the genotoxic agent M-nitroso-N-nitroguanidine (MNNG). Our study also investigated the roles of Ca(2+)-Mg(2+)-dependent endonuclease (CME) in the MNNG-induced nuclear changes. We found that MNNG induced profound ATP depletion as well as marked nuclear condensation and DNA fragmentation in the cells. Both the nuclear condensation and the DNA fragmentation were abolished by posttreatment of the cells with the CME inhibitor aurintricarboxylic acid (ATA). The ATA posttreatment also significantly, but only partially, decreased MNNG-induced cell death. In contrast, pretreatment plus cotreatment with ATA did not affect either MNNG-induced nuclear condensation or cell death. Our study further suggests that ATA does not decrease the cytotoxicity of MNNG by directly inhibiting poly(ADP-ribose) polymerases. Collectively, our observations suggest that MNNG can induce both DNA fragmentation and nuclear condensation in astrocytes by a CME-dependent mechanism, which partially contributes to the genotoxic agent-induced cell death. Published 2008 Wiley-Liss, Inc.
Lu
Huafei
H
Department of Neurology, San Francisco VA Medical Center, University of California at San Francisco, San Francisco, California 94121, USA.
Wei
Gangwei
G
Wang
Dongmin
D
Yung
Patrick
P
Ying
Weihai
W
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects*; D004720:Endonucleases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D051379:Mice; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D008769:Methylnitronitrosoguanidine; D001312:Aurintricarboxylic Acid; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D004720:Endonucleases