The novel Nrf2 activator CDDO‐EA attenuates cerebral ischemic injury by promoting microglia/macrophage polarization toward M2 phenotype in mice

The aim of present study was to explore whether 2‐cyano‐3, 12‐dioxooleana‐1, 9‐dien‐28‐oic acid (CDDO)‐ethylamide (CDDO‐EA) attenuates cerebral ischemic injury and its possible mechanisms using a middle cerebral artery occlusion (MCAO) model in C57BL/6 mice. Our results showed that intraperitoneal injection (i.p.) of CDDO‐EA (2 and 4 mg/kg) augmented NFE2‐related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1) expression in ischemic cortex after MCAO. Moreover, CDDO‐EA (2 mg/kg, i.p.) significantly enhanced Nrf2 nuclear accumulation, associated with increased cytosolic HO‐1 expression, reduced neurological deficit and infarct volume as well as neural apoptosis, and shifted polarization of microglia/macrophages toward an antiinflammatory M2 phenotype in ischemic cortex after MCAO. Using an in vitro model, we confirmed that CDDO‐EA (100 μg/mL) increased HO‐1 expression and primed microglial polarization toward M2 phenotype under inflammatory stimulation in BV2 microglial cells. These findings suggest that a novel Nrf2 activator CDDO‐EA confers neuroprotection against ischemic injury.