Evidence that lipopolysaccharide-induced cell death is mediated by accumulation of reactive oxygen species and activation of p38 in rat cortex and hippocampus.
Lipopolysaccharide (LPS) administration stimulates immune activation, inflammation and deterioration in cell function. Neuronal tissue in cortex and hippocampus are particularly susceptible. In this study, we report that LPS induces cell death as measured by caspase-3 activation and DNA fragmentation and that this is coupled with stimulation of the mitogen-activated protein kinase, p38. We provide evidence of co-localization of activated p38 and caspase-3 in cells prepared from cortical and hippocampal tissue after LPS treatment. Furthermore, administration of the p38 inhibitor, SB203580, abolished the LPS-induced increase in caspase-3 activation. We observed that LPS treatment provoked accumulation of reactive oxygen species (ROS) while in vitro incubation of cortical and hippocampal tissue with H(2)O(2) increased p38 activity. In addition, H(2)O(2)-induced activation of caspase-3 was abrogated by SB203580. We propose, based on the data presented, that the action of LPS to induce cell death in cortex and hippocampus may be mediated by ROS accumulation and activation of p38.
Nolan
Yvonne
Y
Department of Physiology, Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland. nolany@tcd.ie
Vereker
Emily
E
Lynch
Aileen M
AM
Lynch
Marina A
MA
D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C093642:SB 203580