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Carbonyl Reductase 1 Attenuates Ischemic Brain Injury by Reducing Oxidative Stress and Neuroinflammation

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Abstract

Oxidative stress and neuroinflammatory response after the ischemic injury are important pathophysiologic mechanisms that cause brain tissue loss and neurological deficit. This study aims to observe the expression and role of carbonyl reductase 1 (CBR1), an NADPH-dependent oxidoreductase with specificity for carbonyl compounds such as 4-hydroxynonenal (4-HNE), in the brain after ischemic injury and to investigate the influence of CBR1 on ischemia-induced neuroinflammation. CBR1 expresses in the neurons, astrocyte, and microglia in the normal brain. The expression of CBR1 decreased in the ischemic regions following cerebral ischemia, and also reduced in primary neurons after OGD (oxygen-glucose deprivation); however, the expression of CBR1 significantly increased in microglia in the ischemic penumbra. Furthermore, TAT-CBR1 fusion protein played neuroprotective effects in reducing the infarct volume and improving neurological outcomes after ischemic injury. Mechanistically, CBR1 decreased the levels of 4-HNE in the brain after stroke; it also modulated microglial polarization toward the M2 phenotype, which was well-known to confer neuroprotection after ischemic injury. Our results demonstrate that CBR1 provides neuroprotection against ischemic injury by reducing oxidative stress and neuroinflammation, making a promising agent for cerebral ischemia treatment.

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Abbreviations

4-HNE:

4-hydroxynonenal

CBR1:

carbonyl reductase 1

LDH:

lactate dehydrogenase

LPS:

lipopolysaccharide

MCAO:

middle cerebral arteryocclusion

NeuN:

neuronal nuclei

NO:

nitric oxide

OGD:

oxygen-glucose deprivation

rCBF:

regional cortical cerebral blood flow

ROS:

reactive oxygen species

SDR:

the short-chain dehydrogenases/reductase

SERS:

surface-enhanced Raman scattering

TAT-CBR1:

N-tricosanoyltryptamine-CBR1

TTC:

2, 3, 5-triphenyltetrazolium chloride

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Funding

The authors disclosed receipt of the following financial supports for the research, authorship, and publication of this article: This work was supported by grants from the Natural Science Foundation of China (No. 81701179 to L.M. and No. 81870938 to BS), the Fund of Taishan Scholar Project and Fund of Academic Promotion Program of Shandong First Medical University & Shandong Academy of Medical Sciences (No. 2019QL016, No. 2019PT007), and the American Heart Association under the Award Number 10DSG2560122 and internal funds from the PIBDR and Department of Neurology of the University of Pittsburgh to FZ. Leilei Mao was a student at Fudan University and a visiting research scholar at the University of Pittsburgh (2012–2014).

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Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital; Key Laboratory of Cerebral Microcirculation in Universities of Shandong; Brain Science Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China

    Leilei Mao, Kun Wang, Pengjie Zhang, Shihao Ren, Mingfeng Yang & Baoliang Sun

  2. Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Leilei Mao & Feng Zhang

  3. Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China

    Jingyi Sun

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  1. Leilei Mao
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Correspondence to Leilei Mao or Baoliang Sun.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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Supplementary Figure 1.

The expression of CBR1 decreases in primary neurons by oxygen-glucose deprivation (OGD) treatment. Primary rat cortical neurons were subjected to 60 minutes OGD. A. Western blots showing the time course of CBR1 expression in neurons after OGD. n=3 per group. Data are mean ± S.E. **p <0.01 versus control. B. Representative immunohistochemical images of CBR1 expression in neurons after OGD treatment (20X). C. Quantification of CBR1 expression in primary neurons after OGD. n=3 per group. Data are mean ± S.E. *p<0.05, ***p<0.001vs. control. D. Representative images of the normal or dead neurons after OGD (100X). (PNG 15722 kb)

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Mao, L., Wang, K., Zhang, P. et al. Carbonyl Reductase 1 Attenuates Ischemic Brain Injury by Reducing Oxidative Stress and Neuroinflammation. Transl. Stroke Res. 12, 711–724 (2021). https://doi.org/10.1007/s12975-021-00912-6

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