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Diminished Akt phosphorylation in neurons lacking glutathione peroxidase‐1 (Gpx1) leads to increased susceptibility to oxidative stress‐induced cell death
Author(s) -
Taylor Juliet M.,
Ali Uǧur,
Iannello Rocco C.,
Hertzog Paul,
Crack Peter J.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02863.x
Subject(s) - gpx1 , oxidative stress , protein kinase b , programmed cell death , phosphorylation , microbiology and biotechnology , oxidative phosphorylation , glutathione , chemistry , peroxidase , glutathione peroxidase , glutathione reductase , biology , apoptosis , biochemistry , enzyme , superoxide dismutase
We have previously identified an increased susceptibility of glutathione peroxidase‐1 (Gpx1)–/– mice to neuronal apoptosis following mid‐cerebral artery (MCA) occlusion. This study was designed to elucidate the mechanisms involved in elevated neuronal cell death arising from an altered endogenous oxidant state. This was addressed in both an in vitro and in vivo model of oxidative stress in the form of exogenous H 2 O 2 and cerebral ischaemia, respectively. Increased levels of cell death were detected in primary neurons lacking Gpx1 following the addition of exogenous H 2 O 2 . This increased apoptosis correlated with a down‐regulation in the activation of the phospho‐inositide 3‐kinase [PI(3)K]–Akt survival pathway. The importance of this pathway in protecting against H 2 O 2 ‐induced cell death was highlighted by the increased susceptibility of wildtype neurons to apoptosis when treated with the PI(3)K inhibitor, LY294002. The Gpx1–/– mice also demonstrated elevated neuronal cell death following MCA occlusion. Although Akt phosphorylation was detected in the Gpx1–/– brains, activation was not seen in later reperfusion events, as demonstrated in wildtype brains. Previous studies have highlighted the importance of Akt phosphorylation in protecting against neuronal cell death following cerebral ischaemia–reperfusion. Our results suggest that the increased susceptibility of Gpx1–/– neurons to H 2 O 2 ‐induced apoptosis and neuronal cell death in vivo following cerebral ischaemia–reperfusion injury can be attributed in part to diminished activation of Akt. Perturbations in key anti‐apoptotic mechanisms as a result of an altered redox state may have implications in the study of oxidative stress‐mediated neuropathologies.