Pharmacological Induction of Heme Oxygenase-1 by a Triterpenoid Protects Neurons Against Ischemic Injury

• DOI: 10.1161/strokeaha.111.647420
• Publication Date: 2012-03-30T04:43:00Z
• 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
• Keywords: Ischemic injury

Heme oxygenase-1 (HO-1) is an inducible Phase 2 enzyme that degrades toxic heme; its role in cerebral ischemia not fully understood. We hypothesize 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 genes, protects neurons against ischemic injury.Using 3 different models ischemia, including oxygen-glucose deprivation neuronal cultures, global rats, and focal mice, we determined (1) whether induces expression injury; (2) inhibition disrupts neuroprotective effect CDDO-Im.CDDO-Im treatment (50-300 nmol/L) resulted 8-fold cultured protected deprivation. The protection was abolished when cultures were transfected nuclear factor (erythroid-derived 2) like-2-shRNA or coincubated tin protoporphyrin IX, specific inhibitor. In rat model intracerebroventricular infusion (0.5-1.5 μg) augmented hippocampal significant increases CA1 survival after ischemia. To further strengthen clinical relevance treatment, tested effects mouse temporary (60 minutes). Postischemic intraperitoneal injection (10-100 enhanced significantly reduced neurological dysfunction infarct volume. Intracerebroventricular IX ischemia.CDDO-Im confers neuroprotection injury by upregulating HO-1, suggesting enhance may be legitimate strategy for therapeutic intervention stroke.