Pharmacological induction of heme oxygenase-1 by a triterpenoid protects neurons against ischemic injury.

Abstract

BACKGROUND AND PURPOSE:

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: Feng Zhang, Suping Wang, Meijuan Zhang, Zhongfang Weng, Peiying Li, Yu Gan, Lili Zhang, Guodong Cao, Yanqin Gao, Rehana K Leak, Michael B Sporn, Jun Chen
• Journal: Stroke (Stroke) Vol. 43 Issue 5 Pg. 1390-7 (May 2012) ISSN: 1524-4628 [Electronic] United States
• PMID: 22461332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• Imidazoles
• NF-E2-Related Factor 2
• Protective Agents
• Protoporphyrins
• Triterpenes
• Oleanolic Acid
• protoporphyrin IX
• Heme Oxygenase-1

Topics

• Animals
• Brain Infarction (pathology)
• Brain Ischemia (etiology, metabolism, prevention & control)
• Cells, Cultured
• Heme Oxygenase-1 (antagonists & inhibitors, metabolism)
• Hippocampus (drug effects, metabolism, pathology)
• Hypoxia (complications)
• Imidazoles (administration & dosage, pharmacology)
• Infusions, Intraventricular
• Injections, Intraperitoneal
• Mice
• Models, Animal
• NF-E2-Related Factor 2 (metabolism)
• Neurons (drug effects, metabolism, pathology)
• Oleanolic Acid (administration & dosage, analogs & derivatives, pharmacology)
• Protective Agents (administration & dosage, pharmacology)
• Protoporphyrins (pharmacology)
• Rats
• Triterpenes (administration & dosage, pharmacology)
• Up-Regulation (drug effects)