Inhibition of the ERK/MAP kinase pathway attenuates heme oxygenase-1 expression and heme-mediated neuronal injury.
Hemin is an oxidant that accumulates in intracranial hematomas. Its neurotoxicity is increased by its breakdown, which is catalyzed by the heme oxygenase (HO) enzymes. In this study we tested the hypothesis that inhibiting signaling events mediating HO-1 induction would protect cultured cortical neurons from hemin. A fivefold increase in HO-1 expression was observed in mixed neuron-astrocyte cultures 4h after hemin exposure. This was markedly reduced by the ERK pathway inhibitor U0126. The JNK inhibitor SP600125 had a weak but statistically significant effect, while the p38 inhibitor SB239063 was ineffective. Hemin neurotoxicity, as assessed by LDH release, propidium iodide staining, and malondialdehyde assay, was also prevented by U0126 but not by SB239063; SP600125 had little or no effect. Consistent with reduced iron release, ferritin expression was also attenuated by U0126, while cell hemin accumulation was increased. These results suggest that targeting the ERK pathway may prevent HO-1 induction in response to hemin, and reduce neuronal injury.
Benvenisti-Zarom
Luna
L
Department of Emergency Medicine, Thomas Jefferson University, 1020 Sansom Street, Thompson Building, Room 239, Philadelphia, PA 19107, United States.
Chen-Roetling
Jing
J
Regan
Raymond F
RF
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free; D004622:Embryo, Mammalian / Q000166:cytology; D006418:Heme / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006427:Hemin / Q000633:toxicity; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction
D000873:Anthracenes; D002070:Butadienes; D016895:Culture Media, Serum-Free; D007093:Imidazoles; D008565:Membrane Proteins; D009570:Nitriles; D011743:Pyrimidines; C113580:U 0126; C432165:pyrazolanthrone; D006418:Heme; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C105245:heme oxygenase-2; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C406525:SB 239063