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The Novel Nrf2 Activator Omaveloxolone Regulates Microglia Phenotype and Ameliorates Secondary Brain Injury after Intracerebral Hemorrhage in Mice.

ABSTRACT: The polarization of microglia is recognized as a crucial factor in reducing neuroinflammation and promoting hematoma clearance after intracerebral hemorrhage (ICH). Previous studies have revealed that redox components participate in the regulation of microglial polarization. Recently, the novel Nrf2 activator omaveloxolone (Omav) has been validated to improve neurological function in patients with neurodegenerative disorders by regulating antioxidant responses. In this study, we examined the efficacy of Omav in ICH. Omav significantly promoted Nrf2 nuclear accumulation and the expression of HO-1 and NQO1 in BV2 cells. In addition, both in vitro and in vivo experiments showed that Omav treatment inhibited M1-like activation and promoted the activation of the M2-like microglial phenotype. Omav inhibited OxyHb-induced ROS generation and preserved the function of mitochondria in BV2 cells. Intraperitoneal administration of Omav improved sensorimotor function in the ICH mouse model. Importantly, these effects were blocked by pretreatment with ML385, a selective inhibitor of Nrf2. Collectively, Omav modulated microglial polarization by activating Nrf2 and inhibiting ROS generation in ICH models, suggesting that it might be a promising drug candidate for the treatment of ICH.

SUBMITTER: Hu L

PROVIDER: S-EPMC8933082 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The Novel Nrf2 Activator Omaveloxolone Regulates Microglia Phenotype and Ameliorates Secondary Brain Injury after Intracerebral Hemorrhage in Mice.

Hu Libin L Cao Yang Y Chen Huaijun H Xu Lei L Yang Qiguo Q Zhou Hang H Li Jianru J Yu Qian Q Dou Zhangqi Z Li Yin Y Yan Feng F Liu Fuyi F Chen Gao G

Oxidative medicine and cellular longevity 20220311

The polarization of microglia is recognized as a crucial factor in reducing neuroinflammation and promoting hematoma clearance after intracerebral hemorrhage (ICH). Previous studies have revealed that redox components participate in the regulation of microglial polarization. Recently, the novel Nrf2 activator omaveloxolone (Omav) has been validated to improve neurological function in patients with neurodegenerative disorders by regulating antioxidant responses. In this study, we examined the eff ...[more]

PMID: 35308167

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Project description:ImportanceIntracerebral hemorrhage (ICH) contributes significantly to the global burden of disease.ObjectiveTo examine the association of ICH and secondary injury with disability-adjusted life-years (DALYs) for the individual patient.Design, setting, and participantsThis cohort study was conducted using data from the Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage study. Consecutive patients admitted to a single tertiary care center from January 1, 2006, to December 31, 2015, were included. The sample comprised patients with oral anticoagulation-associated ICH (OAC-ICH) or primary spontaneous ICH (non-OAC-ICH). Statistical analysis was conducted from October 1 to December 31, 2020.ExposuresICH occurrence and secondary injury.Main outcomes and measuresDALYs, years of life lost (YLL), and years lived with disability (YLD) were analyzed by hematoma location, ICH volume, and secondary injury (ie, hematoma expansion [HE], intraventricular hemorrhage [IVH], and perihemorrhagic edema [PHE]).ResultsAmong 1322 patients with ICH, 615 (46.5%) were women and the mean (SD) age at hospital admission was 71 (13) years; ICH was associated with a mean (SD) of 9.46 (8.08) DALYs, 5.72 (8.29) YLL, and 3.74 (5.95) YLD. There were statistically significant differences in mean (SD) DALYs by extent of hematoma volume (< 10 mL ICH: 7.05 [6.79] DALYs; 10-30 mL ICH: 9.91 [8.35] DALYs; >30 mL ICH: 12.42 [8.47] DALYs; P < .001) and ICH location (deep location: 10.60 [8.35] DALYs; lobar location: 8.18 [7.63] DALYs; cerebellum: 8.14 [6.80] DALYs; brainstem: 12.63 [9.21] DALYs; P < .001). Regarding population-level disease burden of secondary injuries after ICH, there was a statistically significant difference in mean (SD) by injury type, with 0.94 (3.19) DALYs for HE, 2.45 (4.16) DALYs for IVH, and 1.96 (2.66) DALYs for PHE (P < .001) among the entire ICH cohort. Regarding individual-level exposure to secondary injuries after ICH, there were a mean (SD) 7.14 (6.62) DALYs for HE, 4.58 (4.75) DALYs for IVH, and 3.35 (3.28) DALYs for PHE among patients with ICH affected by secondary injuries.Conclusions and relevanceThese findings suggest that there is a high burden of disability associated with ICH and secondary injuries, and the findings may guide public health strategies. The study findings further suggest that IVH and PHE may be relevant for the overall outcome of patients with ICH, that DALYs may represent a viable outcome parameter for studies to evaluate treatment outcomes in ICH research, and that IVH and PHE may represent potential treatment targets.

Dataset Information

The Novel Nrf2 Activator Omaveloxolone Regulates Microglia Phenotype and Ameliorates Secondary Brain Injury after Intracerebral Hemorrhage in Mice.

Publications

The Novel Nrf2 Activator Omaveloxolone Regulates Microglia Phenotype and Ameliorates Secondary Brain Injury after Intracerebral Hemorrhage in Mice.

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