title: Cellular protection using Flt3 and PI3Kα inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity.
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.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Yunyi
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin, 1400 Barbara Jordan Blvd, Austin, Texas 78723, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Tiziani
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Goonho
authors.initials: G
authors.lastname: Park
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Kaul
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Paternostro
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D018698:Glutamic Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D051941:fms-Like Tyrosine Kinase 3; C484760:PIK3CA protein, human; C497970:FLT3 protein, human
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