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

  • CNS Neurosci Ther. 2021 Jan;27(1):82-91. doi: 10.1111/cns.13496.
Xia Lei  1  2  3 ,  Hanxia Li  1  2 ,  Min Li  1  2 ,  Qiwei Dong  1  2 ,  Huayang Zhao  1  2 ,  Zongyong Zhang  1  2 ,  Baoliang Sun  1  2 ,  Leilei Mao  1  2
Affiliations
  • 1. Department of Neurology, Second Affiliated Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, China.
  • 2. Key Laboratory of Cerebral Microcirculation in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, China.
  • 3. Department of Neurology, Cangzhou People's Hospital, Cangzhou, China.
PMID: 33280237 DOI: 10.1111/cns.13496
Abstract

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.

Keywords
CDDO-EA; HO-1; Nrf2; cerebral ischemia; microglia/macrophage.
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