Feng Zhang1,2,3,4,5, Suping Wang1,2,3,4,5, Meijuan Zhang1,2,3,4,5, Zhongfang Weng1,2,3,4,5, Peiying Li1,2,3,4,5, Yu Gan1,2,3,4,5, Lili Zhang1,2,3,4,5, Guodong Cao1,2,3,4,5, Yanqin Gao1,2,3,4,5, Rehana K. Leak1,2,3,4,5, Michael B. Sporn1,2,3,4,5, Jun Chen1,2,3,4,5
1From the Department of Neurology, Pharmacology (F.Z., S.W., M.Z., Z.W., P.L., Y.G., L.Z., G.C., Y.G., J.C.) and Center of Cerebrovascular Disease Research, University of Pittsburgh, Pittsburgh, PA; the State Key Laboratory of Medical Neurobiology (F.Z., S.W., Z.W., P.L., Y.G., L.Z., G.C., Y.G., J.C.), Fudan University, Shanghai, China; the Division of Pharmaceutical Sciences (R.K.L.), Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA; the Departments of Pharmacology and Medicine (M.B.S.)...
2the Departments of Pharmacology and Medicine (M.B.S.), Dartmouth Medical School, Hanover, NH
3the Division of Pharmaceutical Sciences (R.K.L.), Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA
4the Geriatric Research, Education and Clinical Center (F.Z., S.W., Z.W., L.Z., G.C., J.C.), Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA.
5the State Key Laboratory of Medical Neurobiology (F.Z., S.W., Z.W., P.L., Y.G., L.Z., G.C., Y.G., J.C.), Fudan University, Shanghai, China
Tóm tắt
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.
