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

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 ?g/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.

SUBMITTER: Lei X

PROVIDER: S-EPMC7804925 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Lei Xia X Li Hanxia H Li Min M Dong Qiwei Q Zhao Huayang H Zhang Zongyong Z Sun Baoliang B Mao Leilei L

CNS neuroscience & therapeutics 20201206 1

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 ...[more]

PMID: 33280237

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Project description:BACKGROUND:Immune activation, specifically activation of macrophages and resident microglia, leading to inflammation is a key component in the progression of spinal cord injury (SCI). Macrophages/microglia exist in two states-the classically activated M1 phenotype that confers pro-inflammatory effects or the alternatively activated M2 phenotype that confers anti-inflammatory effects. Ecto-5'-nucleotidase (CD73) is an immunosuppressive molecule intricately involved in adaptive and innate immune responses and is able to dephosphorylate AMP to adenosine. However, it is not known if CD73 is able to modulate the macrophages/microglia transformation between the M1 and M2 phenotypes. METHODS:We used gene-deficient mice to determine the role of CD73 in macrophages/microglia polarization post-SCI in vivo. We used small interference RNA (siRNA) or pcDNA3.1 to inhibit or overexpress CD73 in BV2 cells to verify anterior discovery in vitro. A combination of molecular and histological methods was used to detect the macrophages/microglia polarization and explore the mechanism both in vivo and in vitro. RESULTS:We found that SCI induced the upregulation of CD73 expression. CD73 deficient mice were noted to demonstrate overwhelming immune responses, few anti-inflammatory phenotype macrophages/microglia, and had a poorer locomotor recovery in comparison to wild-type mice that were also inflicted with SCI. In vitro studies found that CD73 suppression inhibited the expression of characteristic microglial anti-inflammatory polarization markers in BV2 cells, while the converse was noted in CD73 overexpression. Subsequent experiments confirmed that CD73 promoted microglia alternative activation by stimulating p38 MAPK. CONCLUSION:We were able to conclude that CD73 imparts neuroprotective effects by mediating macrophages/microglia polarization. These findings allow for better understanding of the modulatory factors involved in triggering the change in macrophages/microglia phenotypes, therefore uncovering additional molecules and pathways that may be targeted in the innovation of novel SCI therapies.

Project description:Background and purposeWhite matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model.MethodsChronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis.ResultsDisruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post-bilateral carotid artery stenosis-induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720's effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling.ConclusionsOur study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.

Project description:Background and purposeSubarachnoid hemorrhage (SAH) is a life-threatening subtype of stroke with high rates of mortality. In the early stages of SAH, neuroinflammation is one of the important mechanisms leading to brain injury after SAH. In various central nervous system diseases, activation of RARα receptor has been proven to demonstrate neuroprotective effects. This study aimed to investigate the anti-inflammatory effects of RARα receptor activation after SAH.MethodsInternal carotid artery puncture method used to established SAH model in Sprague-Dawley rats. The RARα specific agonist Am80 was injected intraperitoneally 1 hour after SAH. AGN196996 (specific RARα inhibitor), Msr1 siRNA and LY294002 (PI3K-Akt inhibitor) were administered via the lateral ventricle before SAH. Evaluation SAH grade, neurological function score, blood-brain barrier permeability. BV2 cells and SH-SY5Y cells were co-cultured and stimulated by oxyhemoglobin to establish an in vitro model of SAH. RT-PCR, Western blotting, and immunofluorescence staining were used to investigate pathway-related proteins, microglia activation and inflammatory response. Results: The expression of RARα, Mafb, and Msr1 increased in rat brain tissue after SAH. Activation of the RARα receptor with Am80 improved neurological deficits and attenuated brain edema, blood brain barrier permeability. Am80 increased the expression of Mafb and Msr1, and reduced neuroinflammation by enhancing the phosphorylation of Akt and by inhibiting the phosphorylation of NF-κB. AGN196996, Msr1 siRNA, and LY294002 reversed the therapeutic effects of Am80 by reducing the expression of Msr1 and the phosphorylation of Akt. In vitro model of SAH, Am80 promoted M1-to-M2 phenotypic polarization in microglia and suppressed the nuclear transcription of NF-κB.ConclusionActivation of the RARα receptor attenuated neuroinflammation by promoting M1-to-M2 phenotypic polarization in microglia and regulating the Mafb/Msr1/PI3K-Akt/NF-κB pathway. RARα might serve as a potential target for SAH therapy.

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

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

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