title: Heme oxygenase-1 (HO-1) upregulation delays morphological and oxidative damage induced in an excitotoxic/pro-oxidant model in the rat striatum.
abstract: Quinolinic acid (QA)-induced overactivation of N-methyl-d-aspartate receptors yields excitotoxicity, oxidative stress and mitochondrial dysfunction, which altogether contribute to trigger a wide variety of toxic pathways with biochemical, behavioral and neuropathological alterations similar to those observed in Huntington's disease. Noteworthy, in the brains of these patients, increased expression of heme oxygenase-1 (HO-1) levels can be found. It has been proposed that this enzyme can exert a dual role, as it can be either protective or deleterious to the CNS. While some evidence indicates that its overexpression affords cellular anti-oxidant protection due to decreased concentrations of its pro-oxidative substrate heme group, and increased bilirubin levels, other reports established that high HO-1 expression and activity may result in a pro-oxidizing atmosphere due to a release of Fe(2+). In this work, we examined the temporal evolution of oxidative damage to proteins, HO-1 expression, immunoreactivity, total activity, and cell death after 1, 3, 5 and 7 days of an intrastriatal QA infusion (240 nmol/μl). QA was found to induce cellular degeneration, increasing carbonylated proteins and generating a transitory response in HO-1 mRNA, protein content, and immunoreactivity and activity in nerve cells. In order to study the role of HO-1 in the QA-induced cellular death, the tin protoporphyrin IX (SnPP), a well-known HO inhibitor, was administered to rats (30 μmol/kg, i.p.). The administration of SnPP to animals treated with QA inhibited the HO activation, and exacerbated the striatal cell damage induced by QA. Our findings reveal a potential modulatory role of HO-1 in the toxic paradigm evoked by QA in rats. This evidence provides a valuable tool for further approaches on HO-1 regulation in neurotoxic paradigms.
authors.affiliation: Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía, Mexico City 14269, Mexico.
authors.forename: A L
authors.initials: AL
authors.lastname: Colín-González
authors.forename: M
authors.initials: M
authors.lastname: Orozco-Ibarra
authors.forename: M E
authors.initials: ME
authors.lastname: Chánez-Cárdenas
authors.forename: E
authors.initials: E
authors.lastname: Rangel-López
authors.forename: A
authors.initials: A
authors.lastname: Santamaría
authors.forename: J
authors.initials: J
authors.lastname: Pedraza-Chaverri
authors.forename: D
authors.initials: D
authors.lastname: Barrera-Oviedo
authors.forename: P D
authors.initials: PD
authors.lastname: Maldonado
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011524:Protoporphyrins / Q000494:pharmacology; D017378:Quinolinic Acid; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D008665:Metalloporphyrins; D018696:Neuroprotective Agents; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1; D017378:Quinolinic Acid