Article

The role of PARP activation in glutamate-induced necroptosis in HT-22 cells.

Institute of Neuroscience, Soochow University, 199 Ren-Ai Road, Suzhou City, Jiangsu Province 215123, PR China.
Brain research (impact factor: 2.46). 05/2010; 1343:206-12. DOI:10.1016/j.brainres.2010.04.080 pp.206-12
Source: PubMed

ABSTRACT 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.

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    Article: Many stimuli pull the necrotic trigger, an overview.
    N Vanlangenakker, T Vanden Berghe, P Vandenabeele
    [show abstract] [hide abstract]
    ABSTRACT: The lab of Jürg Tschopp was the first to report on the crucial role of receptor-interacting protein kinase 1 (RIPK1) in caspase-independent cell death. Because of this pioneer finding, regulated necrosis and in particular RIPK1/RIPK3 kinase-mediated necrosis, referred to as necroptosis, has become an intensively studied form of regulated cell death. Although necrosis was identified initially as a backup cell death program when apoptosis is blocked, it is now recognized as a cellular defense mechanism against viral infections and as being critically involved in ischemia-reperfusion damage. The observation that RIPK3 ablation rescues embryonic lethality in mice deficient in caspase-8 or Fas-associated-protein-via-a-death-domain demonstrates the crucial role of this apoptotic platform in the negative control of necroptosis during development. Here, we review and discuss commonalities and differences of the increasing list of inducers of regulated necrosis ranging from cytokines, pathogen-associated molecular patterns, to several forms of physicochemical cellular stress. Since the discovery of the crucial role of RIPK1 and RIPK3 in necroptosis, these kinases have become potential therapeutic targets. The availability of new pharmacological inhibitors and transgenic models will allow us to further document the important role of this form of cell death in degenerative, inflammatory and infectious diseases.
    Cell death and differentiation 11/2011; 19(1):75-86. · 8.24 Impact Factor
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Keywords

Alzheimer's disease
 
brain trauma
 
cell death
 
cellular apoptosis-inducing factor
 
critical role
 
direct PARP inhibitor
 
downstream target
 
glutamate exposure
 
glutamate-induced necroptosis
 
glutamate-induced oxytosis
 
MNNG-mediated cell death
 
neurological diseases
 
neuronal cell death
 
Oxidative cell death contributes
 
oxidative stress-induced necroptosis
 
PARP activator N-methyl-N'-nitro-N-nitrosoguanidine
 
PARP activity
 
PARP-1 activation
 
protective effect
 
signaling target
 

Xingshun Xu