TY - JOUR
T1 - Hemin-induced necroptosis involves glutathione depletion in mouse astrocytes
AU - Laird, Melissa D.
AU - Wakade, Chandramohan
AU - Alleyne, Cargill H.
AU - Dhandapani, Krishnan M.
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2008/10/15
Y1 - 2008/10/15
N2 - Intracerebral hemorrhage (ICH) is a devastating neurological injury associated with significant mortality. Astrocytic inflammation may contribute to the pathogenesis of ICH, although the underlying cellular mechanisms remain unclear. In this study, the hemoglobin oxidation by-product, hemin, concentration-dependently induced necroptotic cell death in cortical astrocytes within 5 h of treatment. Hemin-induced cell death was preceded by increased inflammatory gene expression (COX-2, IL-1β, TNF-α, iNOS). Inhibition of the NF-κB transcription factor reversed inflammatory gene expression and attenuated cell death after hemin treatment, suggesting a possible role for inflammatory mediators in astrocytic injury. Superoxide production paralleled the increase in iNOS expression, and inhibition of either iNOS (aminoguanidine or iminopiperdine) or superoxide (apocynin) significantly reduced cell death. Similarly, reduced formation of peroxynitrite, the damaging product of nitric oxide and superoxide, significantly reduced hemin injury. Hemin-induced peroxidative injury was associated with a rapid depletion of intracellular glutathione (GSH), culminating in lipid peroxidation and cell death, effects that were reduced by cotreatment with exogenous GSH, N-acetyl-l-cysteine, or the glutathione peroxidase mimetic ebselen. Together, these studies suggest a novel role for GSH depletion in necroptotic astrocyte injury after a hemorrhagic injury and indicate that therapeutic targeting of GSH may exert a beneficial effect after ICH.
AB - Intracerebral hemorrhage (ICH) is a devastating neurological injury associated with significant mortality. Astrocytic inflammation may contribute to the pathogenesis of ICH, although the underlying cellular mechanisms remain unclear. In this study, the hemoglobin oxidation by-product, hemin, concentration-dependently induced necroptotic cell death in cortical astrocytes within 5 h of treatment. Hemin-induced cell death was preceded by increased inflammatory gene expression (COX-2, IL-1β, TNF-α, iNOS). Inhibition of the NF-κB transcription factor reversed inflammatory gene expression and attenuated cell death after hemin treatment, suggesting a possible role for inflammatory mediators in astrocytic injury. Superoxide production paralleled the increase in iNOS expression, and inhibition of either iNOS (aminoguanidine or iminopiperdine) or superoxide (apocynin) significantly reduced cell death. Similarly, reduced formation of peroxynitrite, the damaging product of nitric oxide and superoxide, significantly reduced hemin injury. Hemin-induced peroxidative injury was associated with a rapid depletion of intracellular glutathione (GSH), culminating in lipid peroxidation and cell death, effects that were reduced by cotreatment with exogenous GSH, N-acetyl-l-cysteine, or the glutathione peroxidase mimetic ebselen. Together, these studies suggest a novel role for GSH depletion in necroptotic astrocyte injury after a hemorrhagic injury and indicate that therapeutic targeting of GSH may exert a beneficial effect after ICH.
KW - Astrocyte
KW - Free
KW - Hemin
KW - Hemorrhage
KW - Inflammation
KW - Peroxynitrite
KW - iNOS
KW - radicals
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U2 - 10.1016/j.freeradbiomed.2008.07.003
DO - 10.1016/j.freeradbiomed.2008.07.003
M3 - Article
C2 - 18706498
AN - SCOPUS:53049083456
SN - 0891-5849
VL - 45
SP - 1103
EP - 1114
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 8
ER -