Necrostatin-1 Protects Against Glutamate-Induced Glutathione Depletion and Caspase-Independent Cell Death in HT-22 Cells
Document Type
Article
Publication Date
12-1-2007
Description
Glutamate, a major excitatory neurotransmitter in the CNS, plays a critical role in neurological disorders such as stroke and Parkinson's disease. Recent studies have suggested that glutamate excess can result in a form of cell death called glutamate-induced oxytosis. In this study, we explore the protective effects of necrostatin-1 (Nec-1), an inhibitor of necroptosis, on glutamate-induced oxytosis. We show that Nec-1 inhibits glutamate-induced oxytosis in HT-22 cells through a mechanism that involves an increase in cellular glutathione (GSH) levels as well as a reduction in reactive oxygen species production. However, Nec-1 had no protective effect on free radical-induced cell death caused by hydrogen peroxide or menadione, which suggests that Nec-1 has no antioxidant effects. Interestingly, the protective effect of Nec-1 was still observed when cellular GSH was depleted by buthionine sulfoximine, a specific and irreversible inhibitor of glutamylcysteine synthetase. Our study further demonstrates that Nec-1 significantly blocks the nuclear translocation of apoptosis-inducing factor (a marker of caspase-independent programmed cell death) and inhibits the integration of Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (a pro-death member of the Bcl-2 family) into the mitochondrial membrane. Taken together, these results demonstrate for the first time that Nec-1 prevents glutamate-induced oxytosis in HT-22 cells through GSH related as well as apoptosis-inducing factor and Bcl-2/adenovirus E1B 19 kDa-interacting protein 3-related pathways.
Citation Information
Xu, Xingshun; Chua, Chu C.; Kong, Jiming; Kostrzewa, Richard M.; Kumaraguru, Udayasankar; Hamdy, Ronald C.; and Chua, Balvin H.L.. 2007. Necrostatin-1 Protects Against Glutamate-Induced Glutathione Depletion and Caspase-Independent Cell Death in HT-22 Cells. Journal of Neurochemistry. Vol.103(5). 2004-2014. https://doi.org/10.1111/j.1471-4159.2007.04884.x PMID: 17760869 ISSN: 0022-3042