Pharmacological Induction of Heme Oxygenase-1 by a Triterpenoid Protects Neurons Against Ischemic Injury
Brain Infarction
Neurons
0303 health sciences
NF-E2-Related Factor 2
Imidazoles
Protoporphyrins
Protective Agents
Hippocampus
Triterpenes
Brain Ischemia
Rats
Up-Regulation
3. Good health
Mice
03 medical and health sciences
Infusions, Intraventricular
Models, Animal
Animals
Oleanolic Acid
Hypoxia
Cells, Cultured
Heme Oxygenase-1
Injections, Intraperitoneal
DOI:
10.1161/strokeaha.111.647420
Publication Date:
2012-03-30T04:43:00Z
AUTHORS (12)
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.
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CITATIONS (78)
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