title: Oxidative stress is related to the deleterious effects of heme oxygenase-1 in an in vivo neuroinflammatory rat model.
abstract: Heme oxygenase-1 (HO-1) induction is associated with beneficial or deleterious effects depending on the experimental conditions adopted and the neurodegenerative rodent models used. The present study aimed first to evaluate the effects of cerebral HO-1 induction in an in vivo rat model of neuroinflammation by intrastriatal injection of quinolinic acid (QA) and secondly to explore the role played by reactive oxygen species (ROS) and free iron (Fe(2+)) derived from heme catabolism promoted by HO-1. Chronic I.P. treatment with the HO-1 inductor and substrate hemin was responsible for a significant dose-related increase of cerebral HO-1 production. Brain tissue loss, microglial activation, and neuronal death were significantly higher in rats receiving QA plus hemin (H-QA) versus QA and controls. Significant increase of ROS production in H-QA rat brain was inhibited by the specific HO-1 inhibitor ZnPP which supports the idea that ROS level augmentation in hemin-treated animals is a direct consequence of HO-1 induction. The cerebral tissue loss and ROS level in hemin-treated rats receiving the iron chelator deferoxamine were significantly decreased, demonstrating the involvement of Fe(2+)in brain ROS production. Therefore, the deleterious effects of HO-1 expression in this in vivo neuroinflammatory model were linked to a hyperproduction of ROS, itself promoted by free iron liberation.
authors.affiliation: UMR INSERM U930, Université François Rabelais de Tours, PRES Centre Val de Loire Université, 37000 Tours, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Tronel
authors.forename: Gaël Y
authors.initials: GY
authors.lastname: Rochefort
authors.forename: Nicolas
authors.initials: N
authors.lastname: Arlicot
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bodard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.forename: Daniel
authors.initials: D
authors.lastname: Antier
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D004195:Disease Models, Animal; D005296:Ferrous Compounds / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D006427:Hemin; D051547:Heme Oxygenase-1; D017378:Quinolinic Acid