The role of PARP activation in glutamate-induced necroptosis in HT-22 cells.
Oxidative cell death contributes to neuronal cell death in many neurological diseases such as stroke, brain trauma, and Alzheimer's disease. In this study, we explored the involvement of poly(ADP-ribose)-polymerase (PARP) in oxidative stress-induced necroptosis. We showed that PJ34, a potent and specific inhibitor of PARP, can completely inhibit glutamate-induced necroptosis in HT-22 cells. This protective effect was still observed 8h after glutamate exposure followed by PJ34 treatment. These results suggest that PARP activation plays a critical role in glutamate-induced necroptosis. We also examined the interaction between PARP and a necroptosis inhibitor called necrostatin-1 (Nec-1). Previously, we showed that Nec-1 protects against glutamate-induced oxytosis by inhibiting the translocation of cellular apoptosis-inducing factor (AIF), a downstream target of PARP-1 activation. In this study, Nec-1 reduced PARP activity but had no effect on the expression of PARP-1 in cells treated with glutamate. Nec-1 also did not protect against cell death mediated by the PARP activator N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), although PJ34 did protect against MNNG-mediated cell death. These findings suggest that Nec-1 is not a direct PARP inhibitor and that its signaling target is located upstream of PARP.
Xu
Xingshun
X
Institute of Neuroscience, Soochow University, 199 Ren-Ai Road, Suzhou City, Jiangsu Province 215123, PR China. Xingshunxu@suda.edu.cn
Chua
Chu C
CC
Zhang
Min
M
Geng
Deqin
D
Liu
Chun-Feng
CF
Hamdy
Ronald C
RC
Chua
Balvin H L
BH
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051379:Mice; D009336:Necrosis; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009498:Neurotoxins / Q000378:metabolism / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism* / Q000502:physiology
D051033:Apoptosis Inducing Factor; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D009498:Neurotoxins; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C507699:necrostatin-1; D008769:Methylnitronitrosoguanidine; D018698:Glutamic Acid; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases