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 8 h 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.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:etsu-works-17948 |
| Date | 09 July 2010 |
| Creators | Xu, Xingshun, Chua, Chu C., Zhang, Min, Geng, Deqin, Liu, Chun F., Hamdy, Ronald C., Chua, Balvin H.L. |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Detected Language | English |
| Type | text |
| Source | ETSU Faculty Works |
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