Cellular protection using Flt3 and PI3Kα inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity

Yunyi Kang, Stefano Tiziani, Goonho Park, Marcus Kaul and Giovanni Paternostro ()
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Yunyi Kang: Sanford-Burnham Medical Research Institute
Stefano Tiziani: Dell Pediatric Research Institute, University of Texas at Austin
Goonho Park: Sanford-Burnham Medical Research Institute
Marcus Kaul: Sanford-Burnham Medical Research Institute
Giovanni Paternostro: Sanford-Burnham Medical Research Institute

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Glutamate-induced oxidative stress is a major contributor to neurodegenerative diseases. Here, we identify small-molecule inhibitors of this process. We screen a kinase inhibitor library on neuronal cells and identify Flt3 and PI3Kα inhibitors as potent protectors against glutamate toxicity. Both inhibitors prevented reactive oxygen species (ROS) generation, mitochondrial hyperpolarization and lipid peroxidation in neuronal cells, but they do so by distinct molecular mechanisms. The PI3Kα inhibitor protects cells by inducing partial restoration of depleted glutathione levels and accumulation of intracellular amino acids, whereas the Flt3 inhibitor prevents lipid peroxidation, a key mechanism of glutamate-mediated toxicity. We also demonstrate that glutamate toxicity involves a combination of ferroptosis, necrosis and AIF-dependent apoptosis. We confirm the protective effect by using multiple inhibitors of these kinases and multiple cell types. Our results not only identify compounds that protect against glutamate-stimulated oxidative stress, but also provide new insights into the mechanisms of glutamate toxicity in neurons.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4672

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DOI: 10.1038/ncomms4672

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