title: Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury.
abstract: OBJECTIVE
  Heme oxygenase-1 (HO-1) is an inducible Phase 2 enzyme that degrades toxic heme; its role in cerebral ischemia is not fully understood. We hypothesize that chemically induced HO-1 upregulation with the novel triterpenoid CDDO-Im (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline), a robust inducer of Phase 2 genes, protects neurons against ischemic injury.
  
  
  METHODS
  Using 3 different models of ischemia, including oxygen-glucose deprivation in neuronal cultures, global ischemia in rats, and focal ischemia in mice, we determined (1) whether CDDO-Im induces HO-1 expression and protects against ischemic injury; and (2) whether HO-1 inhibition disrupts the neuroprotective effect of CDDO-Im.
  
  
  RESULTS
  CDDO-Im treatment (50-300 nmol/L) resulted in 8-fold HO-1 upregulation in cultured neurons and protected against oxygen-glucose deprivation. The protection was abolished when the cultures were transfected with nuclear factor (erythroid-derived 2) like-2-shRNA or coincubated with tin protoporphyrin IX, a specific HO-1 inhibitor. In the rat model of global ischemia, intracerebroventricular infusion of CDDO-Im (0.5-1.5 μg) augmented HO-1 expression in hippocampal neurons and resulted in significant increases in CA1 neuronal survival after global ischemia. To further strengthen the clinical relevance of the CDDO-Im treatment, we tested its effects in the mouse model of temporary focal ischemia (60 minutes). Postischemic intraperitoneal injection of CDDO-Im (10-100 μg) enhanced HO-1 expression and significantly reduced neurological dysfunction and infarct volume. Intracerebroventricular infusion of tin protoporphyrin IX reduced the neuroprotective effect of CDDO-Im against global and focal ischemia.
  
  
  CONCLUSIONS
  CDDO-Im confers neuroprotection against ischemic injury by upregulating HO-1, suggesting that enhance of HO-1 expression may be a legitimate strategy for therapeutic intervention of stroke.
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA. zhanfx2@upmc.edu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Suping
authors.initials: S
authors.lastname: Wang
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zhang
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Weng
authors.forename: Peiying
authors.initials: P
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Gan
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Guodong
authors.initials: G
authors.lastname: Cao
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000473:pathology; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000150:complications; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D057967:Infusions, Intraventricular; D007274:Injections, Intraperitoneal; D051379:Mice; D023421:Models, Animal; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D007093:Imidazoles; D051267:NF-E2-Related Factor 2; D020011:Protective Agents; D011524:Protoporphyrins; D014315:Triterpenes; D009828:Oleanolic Acid; C028025:protoporphyrin IX; D051547:Heme Oxygenase-1