Inflammatory response and glutathione peroxidase in a model of stroke.
Stroke is one of the leading causes of death in major industrial countries. Many factors contribute to the cellular damage resulting from ischemia/reperfusion (I/R). Experimental data indicate an important role for oxidative stress and the inflammatory cascade during I/R. We are testing the hypothesis that the mechanism of protection against I/R damage observed in transgenic mice overexpressing human antioxidant enzymes (particularly intracellular glutathione peroxidase) involves the modulation of inflammatory response as well as reduced sensitivity of neurons to cytotoxic cytokines. Transgenic animals show significant reduction of expression of chemokines, IL-6, and cell death-inducing ligands as well as corresponding receptors in a focal cerebral I/R model. Reduction of DNA binding activity of consensus and potential AP-1 binding sites in mouse Fas ligand promoter sequence was observed in nuclear extracts from transgenic mice overexpressing intracellular glutathione peroxidase compared with normal animals following I/R. This effect was accompanied by modulation of the c-Jun N-terminal kinase/stress-activated protein kinase pathway. Cultured primary neurons from the transgenic mice demonstrated protection against hypoxia/reoxygenation injury as well as cytotoxicity after TNF-alpha and Fas ligand treatment. These results indicate that glutathione peroxidase-sensitive reactive oxygen species play an important role in regulation of cell death during cerebral I/R by modulating intrinsic neuronal sensitivity as well as brain inflammatory reactions.
Ishibashi
Nobuya
N
Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, and Neurotoxicology Laboratories, Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, USA.
Prokopenko
Olga
O
Reuhl
Kenneth R
KR
Mirochnitchenko
Oleg
O
D000818:Animals; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D053222:Fas Ligand Protein; D005979:Glutathione Peroxidase / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D048670:MAP Kinase Kinase 4; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D020556:Neutrophil Infiltration; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D020521:Stroke / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000094765:Glutathione Peroxidase GPX1
D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005979:Glutathione Peroxidase; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse